Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS4352883 A
Publication typeGrant
Application numberUS 06/024,600
Publication dateOct 5, 1982
Filing dateMar 28, 1979
Priority dateMar 28, 1979
Also published asCA1145258A1, DE3012233A1, DE3012233C2
Publication number024600, 06024600, US 4352883 A, US 4352883A, US-A-4352883, US4352883 A, US4352883A
InventorsFranklin Lim
Original AssigneeDamon Corporation
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Encapsulation of biological material
US 4352883 A
Abstract
A core material such as living tissue, individual cells, hormones, enzymes or antibodies is encapsulated in a semipermeable membrane that is permeable to small molecules for contact with the core material but is impermeable to potentially deleterious large molecules. Encapsulation may be carried out by suspending the core material in an aqueous medium containing a water soluble gum that can be reversibly gelled, forming the suspension into droplets, contacting the droplets with a solution of multivalent cations to gel the droplets as discrete, shape-retaining, water insoluble temporary capsules and cross-linking a surface layer of the temporary capsules to produce a semipermeable membrane around the capsules. Optionally the gel within the membrane may be reliquified by removing multivalent cations from the gel.
Images(1)
Previous page
Next page
Claims(22)
What is claimed is:
1. A process for encapsulating viable tissue within a semipermeable membrane, said process comprising the steps of:
A. suspending finely divided living tissue in an aqueous medium which is physiologically compatible with the tissue and which contains a water soluble substance which
(a) is physiologically compatible with the tissue;
and
(b) can be reversibly gelled to form a coherent, shape-retaining mass;
B. forming the suspension into droplets of a size sufficient to envelop tissue;
C. gelling the droplets to form discrete, shape-retaining temporary capsules;
D. forming a permanent semipermeable membrane about the temporary capsules; and
E. reliquifying the gel within the membrane.
2. A process for encapsulating a core material within a semipermeable membrane, said process comprising the steps of:
A. placing the material in a solution of a water-soluble substance that can be reversibly gelled;
B. forming the solution into droplets;
C. gelling the droplets to produce discrete shape-retaining temporary capsules;
D. forming semipermeable membranes about the temporary capsules; and
E. reliquifying the gel within said membranes.
3. The process of claim 2 wherein said substance comprises a gum.
4. The process of claim 3 wherein said gum has free acid groups and said membrane formation step is effected by contacting the temporary capsules with a polymer of a molecular weight between 3000 and 100,000 daltons and having free amino groups, said contacting being effective to form permanent polymer crosslinks between acid groups in a surface layer of the capsule.
5. The process of claim 4 wherein the polymer used for crosslinking is selected from the group consisting of polylysine and polyethylenimine, said polymer having an average molecular weight of about 35,000 daltons.
6. The process of claim 2 wherein the membrane is formed by an interfacial polymerization wherein the temporary capsules are used as a core material in the aqueous phase of a water-in-oil emulsion.
7. The process of claim 6 wherein the reactants used in the polymerizatiion are selected from the group consisting of water soluble polyols, diols, polyamines, and diamines, and water immiscible diacid halides, diacids, and multifunctional sulfonyl halides.
8. The process of claim 6 wherein the interfacial polymerization is a polyaddition reaction.
9. The process of claim 2 wherein the material is selected from the group consisting of enzymes, immunoproteins, activated charcoal particles, and viable tissue.
10. The process of claim 3 wherein the gum is an alkali metal alginate.
11. The process of claim 3 wherein the gum comprises a polysaccharide containing free acid groups.
12. The process of claim 2 wherein said core material is selected from the group consisting of hormones, enzymes and antibodies.
13. A process for encapsulating a core material within a membrane permeable to proteins of a molecular weight no greater than about 100 thousand daltons, said process comprising the steps of:
A. suspending the core material in an aqueous medium which contains a water-soluble gum containing acid groups;
B. forming the suspension into droplets;
C. subjecting the droplets to a solution of multivalent, cations to gel the droplets as discrete, shape-retaining, water insoluble temporary capsules; and
D. permanently cross-linking surface layers of said temporary capsules to produce a semipermeable membrane about said droplets by subjecting them to a polymer containing substitutents reactive with the acid groups of said gum, said polymer having a molecular weight within the range of 3000-100,000 daltons.
14. The process of claim 13 comprising the additional step of resolubilizing the gel within said capsules.
15. The process of claim 13 wherein the water soluble gum is sodium alginate and multivalent cation solution is a calcium solution.
16. The process of claim 15 including the additional step of removing the calcium ions contained within said capsules to resolubilize the gelled alginate interior of the membranes of said capsules.
17. The process of claim 15 wherein said core material is a mammalian tissue selected from the group consisting of Islets of Langerhans, liver, and individual cells thereof and said medium is a physiologically compatible tissue medium.
18. The process of claim 13 wherein said core material is a mammalian tissue selected from the group consisting of Islets of Langerhans, liver, and individual cells thereof and said medium is a physiologically compatible tissue medium.
19. The process of claim 13 wherein said core material comprises living tissue and said aqueous medium is a complete tissue culture medium sufficient to maintain said tissue in vitro.
20. The process of claim 13 wherein said cross-linking polymer is selected from the group consisting of polylysine and and polyethylenimine.
21. The process of claim 20 wherein the average molecular weight of said polymer is about 35,000 daltons.
22. The process of claim 13 wherein said forming step is effected by forcing droplets of the suspension through a capillary tube while vibrating the tube within the center of a vortex formed by imparting circular fluid motion to an aqueous solution containing multi-valent cations.
Description
REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of copending U.S. application Ser. No. 953,413, filed Oct. 23, 1978, now abandoned, the disclosure of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

This invention relates to a process for encapsulating tissue or individual cells so that they remain viable and in a protected state within a membrane which is permeable to nutrients, ions, oxygen, and other materials needed to both maintain the tissue and support its normal metabolic functions, but impermeable to bacteria, lymphocytes, and large proteins of the type responsible for immuochemical reactions resulting in rejection. The process enables the production of, for example, an insulin producing system or other hormone producing system as it allows encapsulation of mammalian pancreatic beta cells, alpha cells, intact islets of Langerhans, and other tissues or tissue fractions which secrete hormones. The capsules may be suspended in a culture medium and will excrete hormone over an extended period. The capsules may also be used as an artificial pancreas which can be implanted, e.g., by injection, into a diabetic mammal and will function in vivo to excrete insulin and other hormones in response to ambient sugar concentration.

it is believed that the art is devoid of methods for encapsulating living tissue such that the tissue remains viable. Attempts to accomplish this are frustrated by the conditions required for capsular membrane formation which are typically hostile to living systems. Copending U.S. application Ser. No. 606,166, to F. Lim et al., filed Aug. 20, 1975, the disclosure of which is incorporated herein by reference, discloses a technique for encapsulating labile biological materials within a semipermeable membrane. This technique is capable, for example, of encapsulating enzymes within a membrane from which the enzyme cannot escape, while allowing free passage of the enzyme's substrate. However, while the technique involves reaction conditions which preserve the fragile operability of biological materials, no suggestion is made that living tissue can be encapsulated.

Encapsulated live cells, organelles, or tissue have many potential uses. For example, within a semipermeable membrane, the encapsulated living material can be preserved in a permanent sterile environment and can be shielded from direct contact with large, potentially destructive molecular species, yet will allow free passage of lower molecular weight tissue nutrients and metabolic products. Thus, the development of such an encapsulation technique could lead to systems for producing useful hormones such as insulin. In such systems, the mammalian tissue responsible for the production of the material would be encapsulated in a manner to allow free passage of nutrients and metabolic products across the membrane, yet prohibit the passage of bacteria. If membrane permeability could be controlled, it is possible that this approach could also lead to artificial organs which could be implanted in a mammalian body, e.g., a diabetic, without rejection and with controlled hormone release, e.g., insulin release triggered by glucose concentration.

Various attempts have been made to produce artificial organs suitable for implantation in mammalian bodies by providing a mechanical semipermeable barrier, e.g., a Millipore diffusion chamber or a capillary tube chamber, about tissue excised from a donor. Such artificial organs normally require surgical implantation. Furthermore, the protective mechanisms of mammalian bodies isolate the implant, typically by plugging pores by fibroblastic overgrowth.

SUMMARY OF THE INVENTION

In one aspect, the instant invention provides a method of encapsulating core material such as living tissue, individual cells, or biologically active materials in a semipermeable membrane. The basic approach involves suspending the tissue to be encapsulated in a physiologically compatible medium containing a water soluble substance that can be made insoluble in water, that is, gelled, to provide a temporary protective environment for the tissue. The medium is next formed into droplets containing the tissue and gelled, for example, by changing conditions of temperature, pH, or ionic environment. The "temporary capsules" thereby produced are then subjected to a treatment, which can be a known treatment, that results in the production of membranes of a controlled permeability (including impermeability) about the shape-retaining temporary capsules.

The temporary capsules can be fabricated from any nontoxic, water soluble substance that can be gelled to form a shape retaining mass by a change of conditions in the medium in which it is placed, and also comprises plural groups which are readily ionized to form anionic or cationic groups. The presence of such groups in the polymer enables surface layers of the capsule to be cross-linked to produce a "permanent" membrane when exposed to polymers containing multiple functionalities of the opposite charge.

The presently preferred material for forming the temporary capsules is polysaccharide gums, either natural or synthetic, of the type which can be (a) gelled to form a shape retaining mass by being exposed to a change in conditions such as a pH change or by being exposed to multivalent cations such as Ca++; and (b) permanently "crosslinked" or hardened by polymers containing reactive groups such as amine or imine groups which can react with acidic polysaccharide constituents. The presently preferred gum is alkali metal alginate. Other water soluble gums which may be used include guar gum, gum arabic, carrageenan, pectin, tragacanth gum, xanthan gum or acidic fractions thereof. When encapsulating thermally refractory materials, gelatin or agar may be used in place of the gums.

The preferred method of formation of the droplets is to force the gum-nutrient-tissue suspension through a vibrating capillary tube placed within the center of the vortex created by rapidly stirring a solution of a multivalent cation. Droplets ejected from the tip of the capillary immediately contact the solution and gel as spheroidal shaped bodies.

The preferred method of forming a permanent semipermeable membrane about the temporary capsules is to "crosslink" surface layers of a gelled gum of the type having free acid groups with polymers containing acid reactive groups such as amine or imine groups. This is typically done in a dilute solution of the selected polymer. Generally, the lower the molecular weight of the polymer, the greater the penetration into the surface of the temporary capsule, and the greater the penetration, the less permeable the resulting membrane. Permanent crosslinks are produced as a consequence of salt formation between the acid reactive groups of the crosslinking polymer and the acid groups of the polysaccharide gum. Within limits, semipermeability can be controlled by setting the molecular weight of the crosslinking polymer, its concentration, and the duration of reaction. Crosslinking polymers which have been used with success include polyethylenimine and polylysine. Molecular weight can vary, depending on the degree of permeability required, between about 3,000 and 100,000 or more. Good results have been obtained using polymers having an average molecular weight on the order of 35,000.

The capsules can be engineered to have a selected in vivo useful life by astute selection of the cross-linking polymer. Proteins or polypeptide crosslinkers, e.g., polylysine, are readily attached in vivo resulting in relatively rapid destruction of the membrane. Cross-linkers not readily digestible in mammalian bodies, e.g., polyethyleneimine, result in longer lasting membranes. By selecting the crosslinking polymer or by cross-linking simultaneously or sequentially with two or more such materials, it is possible to preselect the length of time the implanted tissue remains protected.

Optionally, with certain materials used to form the temporary capsules, it is possible to improve mass transfer within the capsule after formation of the permanent membrane by re-establishing the conditions under which the material is liquid, e.g., removing the multivalent cation. This can be done by ion exchange, e.g., immersion in phosphate buffered saline or citrate buffer. In some situations, such as where it is desired to preserve the encapsulated tissue, or where the temporary gelled capsule is permeable, it may be preferable to leave the encapsulated gum in the crosslinked, gelled state.

An alternative method of membrane formation involves an interfacial polycondensation of polyaddition similar to the procedure disclosed in U.S. application Ser. No. 606,166. This approach involves preparing a suspension of temporary capsules in an aqueous solution of the water soluble reactant of a pair of complementary monomers which can form a polymer. Thereafter, the aqueous phase is suspended in a hydrophobic liquid in which the complementary reactant is soluble. When the second reactant is added to the two-phase system, polymerization takes place at the interface. Permeability can be controlled by controlling the makeup of the hydrophobic solvent and the concentration of the reactants. Still another way to form a semipermeable membrane is to include a quantity of protein in the temporary capsule which can thereafter be crosslinked in surface layers by exposure to a solution of a crosslinking agent such as gluteraldehyde.

The foregoing process has been used to encapsulate viable Islets of Langerhans which, in a medium containing the nutrients and other materials necessary to maintain viability and support in vitro metabolism of the tissue, excrete insulin in the presence of glucose. Encapsulated tissue has been maintained in a viable state for three months. Also, liver cells have been encapsulated and have been demonstrated to be in a physiologically active state.

In another aspect, the instant invention provides a tissue implantation method which does not require surgery and which overcomes many of the problems of immune rejection. In accordance with the invention, the capsules are injected into a suitable site in a mammalian body, and function normally until the tissue expires, or until natural body processes succeed in isolating the capsules so that substances required for viability of the tissue are no longer available. At this point, because surgery is not required for the implant, fresh tissue may be readily provided by another injection. The mammalian body may accordingly be provided with the specialized function of the tissue as long as desired.

In a preferred embodiment of the invention, mammalian Islets of Langerhans, or islet preparations containing selected amounts of alpha, beta, and/or delta cells from islets are encapsulated in polylysine and polyethyleneimine cross-linked alginate membranes. These may be periodically injected, e.g., into the peritoneal cavity of a diabetic mammalian body and function as an artificial pancreas.

Accordingly, it is a primary object of the invention to provide a method of encapsulating living cells, organelles, or tissue in a membrane permeable to the nutrients and other substances needed for maintenance and metabolism and to metabolic products, but impermeable to bacteria and to substances having a molecular weight above a selected level, so as to exclude agents responsible for immunological rejection of the foreign tissue. Other objects of the invention include the provision of encapsulated living tissue useful for producing hormones such as insulin and for effecting complex chemical changes characteristic of the in vivo tissue, to provide an insulin generation system, to provide a body fluid detoxifying system, and to provide encapsulated activated charcoal.

Other objects of the invention are to provide a method of implanting living tissue in mammalian bodies and to provide a non-surgical tissue implantation technique. Still another object is to provide a method of encapsulating living tissue which allows the production of capsules having a high surface area to volume ratio and membranes with a preselected in vivo residence time. Another object of the invention is to provide an artificial pancreas.

These and other objects and features of the invention will be apparent from the following description of some preferred embodiments and from the drawing.

BRIEF DESCRIPTION OF THE DRAWING

The sole FIGURE of the drawing schematically illustrates a preferred method of encapsulating living tissue suitable for use in the process of the invention, and the product microcapsule.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The tissue, organelle, or cell to be encapsulated is prepared in accordance with well-known prior art techniques in finely divided form and suspended in an aqueous medium suitable for maintenance and for supporting the ongoing metabolic processes of the particular tissue involved. Media suitable for this purpose are available commercially. The average diameter of the material to be encapsulated can vary widely between less than a micron to several millimeters. Mammalian islets of Langerhans are typically 140 to 200 microns in diameter. Of course, individual cells such as pancreatic beta cells, alpha cells, delta cells, or various ratios thereof, whole islet of Langerhans, individual hepatocytes, organelles, or other tissue units may be encapsulated as desired. Also, microorganisms may be encapsulated as well as non-living materials such as biological materials.

The ongoing viability of such living matter is dependent, inter alia, on the availability of required nutrients, oxygen transfer, absence of toxic substances in the medium, and the pH of the medium. Heretofore, it has not been possible to maintain such living matter in a physiologically compatible environment while simulteneously encapsulating. The problem has been that the conditions required for membrane formation have been lethal or harmful to the tissue, and no method of membrane formation which tissue can survive in a healthy state has been forthcoming. It has now been discovered that certain water soluble substances which are physiologically compatible with living tissue and can be rendered water insoluble to form a shape-retaining, coherent mass can be used to form a "temporary capsule" or protective barrier layer about tissue particles. Such a material is added, typically at low concentration, to the tissue culture medium. The solution is then formed into droplets containing tissue together with its maintenance medium and is immediately rendered water insoluble and gelled, at least in a surface layer. Thereafter, the shape-retaining temporary capsules are provided with a permanent semipermeable membrane. Where the material used to form the temporary capsules permits, the capsule interior may be reliquified after formation of the permanent membrane. This is done by re-establishing the conditions in the medium at which the material is soluble.

The material used to form the temporary capsules may be any non-toxic, water-soluble material which, by a change in the surrounding temperature, pH, or ionic environment or concentration, can be converted to a shape retaining mass. Preferably, the material also contains plural, easily ionized groups, e.g., carboxyl or amino groups, which can react by salt formation with polymers containing plural groups which ionize to form species of opposite charge. As will be explained below, this type of material enables the deposition of a permanent membrane of a selected porosity and a selected in vivo lifespan in surface layers of the temporary capsule.

The presently preferred materials for forming the temporary capsule are water-soluble, natural or synthetic polysaccharide gums. Many such materials are commercially available. They are typically extracted from vegetable matter and are often used as additives to various foods. Sodium alginate is the presently preferred water soluble gum. Other usable gums include guar gum, gum arabic, charageenan, pectin, tragacanth gum, xanthan gum, or their acidic fractions.

These materials comprise glycoside-linked saccharide chains. Many contain free acid groups, which are often present in the alkali metal ion form, e.g., sodium form. If a multivalent ion such as calcium or strontium is exchanged for the alkali metal ion, the liquid, water-soluble polysaccharide molecules are "crosslinked" to form a water insoluble, shape-retaining gel which can be resolubilized on removal of the ions by ion exchange or via a sequestering agent. While essentially any multivalent ion which can form a salt is operable, it is preferred that physiologically compatible ions, e.g., calcium, be employed. This tends to preserve the tissue in the living state. Other multivalent cations can be used for less fragile material.

Other gums can be switched between the water soluble and gelled, water insoluble state simply by changing the pH of the medium in which they are dissolved.

A typical tissue-tissue medium-gum solution composition comprises equal volumes of tissue in its medium and a one to two percent solution of gum in physiological saline. When employing sodium alginate, a 1.0 to 1.5 percent solution has been used with success.

When encapsulating materials which can resist changes in temperature, gelatin or agar may be used to form the temporary capsules. These can be gelled by injection into a low temperature environment. Other water soluble substances such as hydroxyethyl methacrylate may also be used.

In the next step of the encapsulation process, the gum solution containing the tissue is formed into droplets of a desired size. Thereafter, the droplets are immediately gelled to form shape-retaining spherical or spheroidal masses. Apparatus for conducting these latter steps is illustrated at step BC of the drawing. A beaker 10 containing an aqueous solution of multivalent cation, e.g., 1.5 percent CaCl2 solution, is fitted with a magnetic stirring bar 11 and stirrer 12. The stirring mechanism is actuated to produce a vortex 14 having a hollow center 16. A capillary tube 18 of a selected inside diameter is positioned within hollow region 16 of the vortex and fitted with a vibrator 20. The suspension containing tissue and the solubilized gum is fed through the capillary. The effect of surface tension which would induce the formation of relatively large droplets is minimized by the vibrator so that droplets, illustrated at 22, of a size comparable to the inside diameter of the capillary, are shaken off of the capillary tip. These immediately contact the solution where they absorb calcium ions. This results in "crosslinking" of the gel and in the formation of a shape-retaining, high viscosity protective temporary capsule containing the suspended tissue and its medium. The capsules collect in the solution as a separate phase and are separated by aspiration.

In an alternative embodiment of the process, a small amount of polymer of the type used for permanently crosslinking the gum is included in the solution together with the multivalent ions (or other solution capable of gelling the particular gum employed). This results in the formation of permanent crosslinks. Capsules of this type have certain advantages if the goal is to preserve the tissue.

In the next step of the process, a semipermeable membrane is deposited about the surface of the temporary capsules. There are a variety of methods available for effecting this step, some of which are known in the art. For example, interfacial polymerization techniques can be exploited. In interfacial polymerization, a pair of at least difunctional mutually reactive monomers, or a monomer and a relatively low molecular weight polymer, one of which is soluble in polar solents such as water and the other of which is soluble in hydrophobic solvents such as hexane, are caused to react at the interface of an emulsion of the water-in-oil type. In accordance with the procedure disclosed in the Lim et al application noted above, the material to be encapsulated is suspended or dissolved in water together with the water soluble component of the reaction, the aqueous phase is emulsified in a hydrophobic solvent, and the complementary monomer is added to the continuous phase of the system so that polymerization occurs about the aqueous droplets. By controlling the nature of the continuous phase solvent and the concentration of the reactant contained therein, it is possible to exercise control over pore size and to produce semipermeable microcapsules.

This technique may be used in accordance with the instant invention if the water soluble reactant is dissolved in an aqueous solution, and the solution is used to suspend the temporary capsules. This liquid suspension is then emulsified in, for example, hexane, or a hexane-chloroform mix. The complementary monomer is next added, preferably incrementally, to induce interfacial polymerization at the surface of the aqueous droplets. Because of the gelled mass of polysaccharide surrounding the suspended tissue, and especially if suitably buffered polyfunctional amino-group containing polymers such as certain proteins are employed as the water-soluble reactant, the process is such that the tissue survives the encapsulation in a healthy condition. The substances useful in forming membranes with the polyfunctional amines include diacids, diacid halides, and multifunctional sulfonyl halides. In addition to the polyamines, diamines, polyols, and diols may be used. Molecules containing plural amine groups may also be crosslinked with glutaraldehyde to form a membrane. Another useful method of membrane formation is by interfacial polymerization utilizing polyaddition reactions. In this case, for example, multifunctional amines absorbed in surface layers of the temporary capsules are reacted with epichlorohydrin, epoxidized polyesters, or diisocyanate.

The preferred method of forming the membrane, illustrated as step D in the drawing, is to permanently cross link surface layers of the droplets by subjecting them to an aqueous solution of a polymer containing groups reactive with functionalities in the gel molecules. Certain long chain quaternary ammonium salts may be used for this purpose in some circumstances. When acidic gums are used, polymers containing acid reactive groups such as polyethylenimine and polylysine may be used. In this situation, the polysaccharides are crosslinked by interaction between the carboxyl groups and the amine groups. Advantageously, permeability can be controlled by selecting the molecular weight of the crosslinking polymer used. For example, a solution of polymer having a low molecular weight, in a given time period, will penetrate further into the temporary capsules then will a high molecular weight polymer. The degree of penetration of the crosslinker has been correlated with the resulting permeability. In general, the higher the molecular weight and the less penetration, the larger the pore size. Broadly, polymers within the molecular weight range of 3,000 to 100,000 daltons or greater may be used, depending on the duration of the reaction, the concentration of the polymer solution, and the degree of permeability desired. One successful set of reaction conditions, using polylysine of average molecular weight of about 35,000 daltons, involved reaction for two minutes, with stirring, of a physiological saline solution containing 0.0167 percent polylysine. Optimal reaction conditions suitable for controlling permeability in a given system can readily be determined empirically without the excercise of invention.

The selection of the cross-linker(s) also determines the in vivo residence time of the capsules. In the system described above, the permanent capsule membrane comprises polysaccharide (a readily injestible substance), cross-linked with either or both a polypeptide or protein, e.g., polylysine, or a synthetic substance, e.g., polyethyleneimine. Polymers vary with respect to the rate at which they can be dispersed in vivo. Some are digested without difficulty, e.g., protein; others are slowly degraded, and still others remain indefinitely. The process of the invention contemplates cross-linking with one or more polymers to produce capsules having a selected rate of dissolution in vivo, ranging generally between a few hours or days to substantial permanence. The example which follows discloses how to produce capsules which remain intact at least about two months within the peritoneal cavity of rats. However, the invention is not limited to these particular capsule membranes nor to capsules of this degree of in vivo life. In fact, the optimal in vivo life of the microcapsules depends upon the their intended use and their site of implantation. Those skilled in the art will be able to produce microcapsules of a selected in vivo lifespan empirically without the exercise of invention in view of this disclosure.

At this point in the encapsulation, capsules may be collected which comprise a permanent semipermeable membrane surrounding a gelled solution of gum, tissue compatible culture medium, and tissue particles. If the object is simply to preserve the tissue in a protective environment, no further steps need be done. However, if mass transfer is to be promoted within the capsules and across the membranes, it is preferred to reliquify the gel to its water soluble form. This may be done by reestablishing the conditions under which the gum is a liquid, e.g., changing the pH of the medium or removing the calcium or other multifunctional cations used. In the gels which are insoluble in the presence of multivalent cations, the medium in the capsule can be resolubilized simply by immersing the capsules in phosphate buffered saline, which contains alkali metal ions and hydrogen ions. Monovalent ions exchange with the calcium or other multifunctional ions within the gum when, as shown at stage E of the drawing, the capsules are immersed in the solution with stirring. Other salts, e.g. sodium citrate, may be used for the same purpose.

Lastly, depending on the type of semipermeable membrane formation technique employed, it may be desirable to treat the capsules so as to tie up free amino groups or the like which would otherwise impart to the capsules a tendency to clump. This can be done, for example, by immersing the capsules in a solution of sodium alginate.

The invention contemplates the injection of encapsulated, finely divided tissue, multicellular fractions thereof, or individual cells into an appropriate site within a mammalian body for the purpose of providing the body, at least temporarily, with the tissue's specialized physiological function. The procedure has the dual advantages of obviating the need for surgical implantation (although capsules may be implanted surgically if desired) and successfully dealing with the problems of immune rejection and natural physical isolation. Preferably, the capsule membranes consist of substances which are injested after expiration of the tissue. As noted above, this can be accomplished by employing a cross-linker which resists in vivo breakdown so that a given useful in vivo life is attained.

From the foregoing it will be apparent that the encapsulation process and implantation technique of the invention can be practised using a wide variety of reagents and encapsulated materials and can be varied significantly without departing from the scope and spirit of the invention. The following example should accordingly be construed in all respects as illustrative and not in a limiting sense.

EXAMPLE 1

Islets of Langerhans were obtained from rat pancreas and added to a complete tissue culture (CMRL-1969 Connaught Laboratories, Toronto, Canada) at a concentration of approximately 103 islets per milliliter. The tissue culture contains all nutrients needed for continued viability of the islets as well as the amino acids employed by the Beta cells for making insulin. Four-tenths of a milliliter of the islet suspension was then added to a one-half milliliter volume of 1.2 percent sodium alginate (Sigma Chemical Company) in physiological saline.

Next, 80 milliliters of a 1.5 percent calcium chloride solution were placed in a 150 milliliter beaker on a stirrer and stirred at a rate which induced the formation of a vortex having a conical-shaped void at its center. A glass capillary having a gradually decreasing diameter ending in a tip of inside diameter about 300 microns was then fitted with a vibrator (60 cycles per second). The capillary tip was then placed within the center of the vortex, the vibrator turned on, and the sodium alginate-culture medium-tissue suspension was forced therethrough with an infusion pump. Droplets on the order of 300-400 microns in diameter are thrown from the tip of the capillary and immediately enter the calcium solution.

After 10 minutes, the stirrer was turned off and the supernatant solution was removed by aspiration. The gelled capsules were then transferred to a beaker containing 15 ml of a solution comprising one part of a 2% 2 (cyclohexylamino) ethane sulfonic acid solution in 0.6% NaCl (isotonic, ph=8.2) diluted with 20 parts 1% CaCl2. After a 3 minute immersion, the capsules were washed twice in 1% CaCl2.

The capsules were then transferred to a 32 ml solution comprising 1/80 of one percent polylysine (average MW 35,000 AMU) in physiological saline. After 3 minutes, the polylysine solution was decanted. The capsules were then washed with 1% CaCl2, and then suspended for 3 minutes in a solution of polyethyleneimine (MW 40,000-60,000) produced by diluting a stock 3.3% polyethyleneimine solution in morpholino propane sulfonic acid buffer (0.2 M, pH=6) with sufficient 1% CaCl2 to result in a final polymer concentration of 0.12%. The resulting capsules, having permanent semipermeable membranes, are then washed twice with 1% CaCl2, twice with physiological saline, and mixed with 10 ml of a 0.12 percent alginic acid solution.

The capsules resist clumping, and many can be seen to contain islets of Langerhans. Gel on the interior of the capsules is reliquified by immersing the capsules in a mixture of saline and citrate buffer (pH=7.4) for 5 minutes. Lastly, the capsules are suspended in CMLR-69 medium.

Under the microscope, these capsules have an appearance illustrated in the drawing. They comprise a very thin membrane 24 which encircle an islet 26 within which individual cells 28 can be seen. Molecules having a molecular weight up to about 100 thousand can traverse membrane 24. This allows oxygen, amino acids, nutrients, and plasma components used in culture media (e.g., fetal calf plasma components) to reach the islet and allows insulin to be excreted.

EXAMPLE 2

After repeated washings in physiological saline, microcapsules made in accordance with Example 1 containing approximately 15 islets were suspended in 3 milliliters of CMRL-1969. When eight days old, in the presence of 600 mg/dl glucose, the capsules excreted, in one run, 67 microunits/ml insulin in 1.5 hours. In a second run, 68 microunits/ml insulin were produced in the same amount of time. One week old capsules, in the same medium, but in the presence of 100 mg/dl glucose, in a first run, excreted 25 μunits/ml insulin in 1.2 hours, and in a second run, excreted 10 μunits/ml.

EXAMPLE 3

Diabetic rats with blood gluclose levels in the range of 500-700 mg/dl were each treated with approximately 103 islets encapsulated as set forth in Example 1, and suspended in physiological saline. The capsules were introduced by injection into the peritoneal cavity using a number 19 needle fitted to a syringe. Blood sugar levels were assayed daily and uniformly found to be below 300 mg/dl. Animals sacrificed after two months showed no signs of toxic reaction about the site of the implantation. Capsules removed from sacrificed animals after a two-month in vivo life were intact and showed no signs of degredation.

EXAMPLE 4: ENCAPSULATION OF HEPATOCYTES

The procedure of example 1 was repeated except that 0.5 ml of a liver cell suspension in Hank's solution was used in place of the 0.4 ml islet suspension. The ongoing viability of the liver tissue has been demonstrated by the dye exclusion technique (trypan blue exclusion). It is known that liver tissue, in vitro, can ingest toxins from its environment. Accordingly, toxins of a molecular weight low enough to pass through the semipermeable membranes are injested and destroyed by the tissue. Essentially all toxins treated by the liver are low molecular weight materials. However, the toxins may be protein-complexed. Capsular permeability can be varied according to the need.

EXAMPLE 5

The procedure of example 1 is repeated except that particulate activated charcoal is suspended directly in the sodium alginate solution, the half milliliter of tissue suspension is omitted, and polylysine of an average molecular weight of 35,000 is used as a crosslinker. As long as the charcoal particles are smaller than the smallest inside diameter of the capillary used to produce the droplets, charcoal of high surface area surrounded by a semipermeable membrane results. These effectively prohibit the escape of charcoal chips or dust, yet can be used to absorb medium range molecular weight materials (up to about 2,000 daltons) from fluid passed about the capsules.

The operability of the process has been demonstrated with other living cells including red blood cells, using serum as a medium, sperm cells, using semen as the medium, and baker's yeast. Those skilled in the art will appreciate that a variety of other materials can be encapsulated in addition to thoese specifically set forth herein, and that permeability can be controlled as desired for selected applications of the process. Accordingly, other embodiments are within the following claims.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3522346 *May 31, 1968Jul 28, 1970Research CorpNonthrombogenic microcapsules
US3725113 *Dec 17, 1970Apr 3, 1973Research CorpBlood compatible microencapsulated detoxicants and method for making
US3730841 *Mar 24, 1971May 1, 1973American Cyanamid CoEncapsulated carrier bound enzymes
US3733205 *Aug 7, 1970May 15, 1973PfizerEnzymatic removal of diacetyl from fermented beverages
US3827565 *May 16, 1973Aug 6, 1974Matsumura KMethod and device of artificial endocrine pancreas
US3860490 *Apr 4, 1973Jan 14, 1975Nat Patent Dev CorpProcess of subjecting a microorganism susceptible material to a microorganism
Non-Patent Citations
Reference
1 *Chang, T.M.S., Biomedical Applications of Immobilized Enzymes and Proteins, vol. I, Plenum Press, N.Y., 1977, (pp. 69-90 and 147-153).
2 *Tze, et al., Implantable Artificial Endocrine Pancreas Unit Used to Restore Normoglycaemia in the Diabetic Rat, Nature, vol. 264, 1976, (pp. 466-467).
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4418691 *Oct 26, 1981Dec 6, 1983Massachusetts Institute Of TechnologyMethod of promoting the regeneration of tissue at a wound
US4430760 *Dec 18, 1981Feb 14, 1984Collagen CorporationDemineralized bone or dentin in collagen container
US4458678 *Oct 26, 1981Jul 10, 1984Massachusetts Institute Of TechnologyMethod of promoting tissue generation at a wound
US4495288 *Apr 13, 1983Jan 22, 1985Damon Biotech, Inc.Method of culturing anchorage dependent cells
US4505266 *Apr 17, 1984Mar 19, 1985Massachusetts Institute Of TechnologyMethod of using a fibrous lattice
US4530900 *Sep 13, 1982Jul 23, 1985Seragen Diagnostics Inc.Determining soluble antigen in sample; complexing; precipitating
US4537852 *Nov 12, 1981Aug 27, 1985Kabushiki Kaisha Hayashibara Seibutsu Kagaku KenkyujoProcess for the production of human urokinase
US4562663 *Oct 12, 1982Jan 7, 1986Plant Genetics, Inc.Analogs of botanic seed
US4615883 *Oct 23, 1985Oct 7, 1986Plant Genetics, Inc.Hydrogel encapsulated nematodes
US4621053 *Feb 27, 1984Nov 4, 1986Kabushiki Kaisha Hayashibara Seibutsu Kagaku KenkyujoProcess for the production of human peptide hormones
US4647536 *Mar 8, 1983Mar 3, 1987Klaus MosbachMethod of encapsulating biomaterial in bead polymers
US4649109 *Feb 16, 1984Mar 10, 1987Brandeis UniversityMethods for isolating mutant microorganisms from parental populations
US4663286 *Feb 13, 1984May 5, 1987Damon Biotech, Inc.Encapsulation of materials
US4673566 *May 24, 1984Jun 16, 1987Connaught Laboratories LimitedImplantation for long term treatment of disease
US4673650 *Mar 28, 1986Jun 16, 1987Damon Biotech, Inc.Recovering a pure solution of mature encapsulated cells
US4675339 *Apr 29, 1985Jun 23, 1987Nippon Kayaku Kabushiki KaishaNeutralizing, cooling or concentrating an aqueous antifoam age nt-containing solution; crystallization/
US4680174 *May 24, 1984Jul 14, 1987Damon Biotech, Inc.Induction of immune response by immunization with encapsulated antigen-producing cells
US4689293 *Dec 4, 1984Aug 25, 1987Connaught Laboratories LimitedMicroencapsulation of living tissue and cells
US4690682 *Jan 14, 1986Sep 1, 1987Damon Biotech, Inc.Semipermeable microcapsules
US4692284 *Apr 30, 1986Sep 8, 1987Damon Biotech, Inc.Atomizing living culture material
US4696286 *May 22, 1986Sep 29, 1987The Regents Of The University Of CaliforniaNoncytotoxic layer bonded to water insoluble semipermeable layer
US4701326 *May 19, 1986Oct 20, 1987Plant Genetics, Inc.Membrane-coated hydrogel encapsulated nematodes
US4703108 *Mar 26, 1986Oct 27, 1987University Of Medicine & Dentistry Of New JerseyBiodegradable matrix and methods for producing same
US4715143 *Apr 24, 1986Dec 29, 1987Plant Genetics, Inc.Artificial seed coat for botanic seed analogs
US4743545 *Oct 3, 1984May 10, 1988Torobin Leonard BImmobilized cells and enzymes, biosynthesis
US4753799 *Sep 14, 1987Jun 28, 1988Plant Genetics, Inc.Production of hydrogel encapsulated nematodes
US4755468 *Sep 19, 1985Jul 5, 1988Rhone-Poulenc S.A.Inocula of low water activity with improved resistance to temperature and rehydration, and preparation thereof
US4774093 *Jun 25, 1985Sep 27, 1988Fmc CorporationPolysaccharide compositions, preparation and uses
US4778749 *Jun 1, 1984Oct 18, 1988Karyon Technology, Inc.Tissue culture and production in permeable gels
US4789516 *May 14, 1987Dec 6, 1988Damon Biotech, IncMicroencapsulation; reservoir of substance in one or more capsules
US4798786 *May 6, 1982Jan 17, 1989Stolle Research And Development CorporationLiving cells encapsulated in crosslinked protein
US4801529 *Jun 18, 1985Jan 31, 1989Brandeis UniversityIncubation, separation, detection; enzymes, antigens, antibodies
US4803168 *Jun 4, 1986Feb 7, 1989Damon Biotech, Inc.Capsules for viable cells
US4806355 *Jun 8, 1987Feb 21, 1989Connaught Laboratories LimitedMicroencapsulation of living tissue and cells
US4808707 *Jun 8, 1987Feb 28, 1989University Of DelawareModified permeability
US4837285 *Sep 8, 1987Jun 6, 1989MedimatrixCollagen matrix beads for soft tissue repair
US4840891 *Sep 3, 1986Jun 20, 1989Genetic Engineering, Inc.Encapsulation of sperm for artificial insemination
US4886664 *Jun 8, 1983Dec 12, 1989Rhone-Poulenc, S.A.Low-water-activity inocula for biological control
US4892538 *Nov 17, 1987Jan 9, 1990Brown University Research FoundationIn vivo delivery of neurotransmitters by implanted, encapsulated cells
US4898733 *Nov 4, 1985Feb 6, 1990International Minerals & Chemical Corp.Layered, compression molded device for the sustained release of a beneficial agent
US4898734 *Feb 29, 1988Feb 6, 1990Massachusetts Institute Of TechnologyTransdermal drug delivery, vascular grafts, wound-healing films or polymbric porous membrane
US4900556 *Feb 23, 1988Feb 13, 1990Massachusetts Institute Of TechnologySystem for delayed and pulsed release of biologically active substances
US4921757 *Sep 3, 1987May 1, 1990Massachusetts Institute Of TechnologySystem for delayed and pulsed release of biologically active substances
US4923645 *Nov 16, 1987May 8, 1990Damon Biotech, Inc.Sustained release of encapsulated molecules
US4925673 *Aug 14, 1987May 15, 1990Clinical Technologies Associates, Inc.Delivery systems for pharmacological agents encapsulated with proteinoids
US4927761 *Mar 1, 1988May 22, 1990The Secretary Of State For United Kingdom Atomic Energy Authority In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern IrelandMatrix
US4933122 *Feb 12, 1988Jun 12, 1990Kirin Beer Kabushiki KaishaProcess and apparatus for producing beads
US4933185 *Jul 11, 1988Jun 12, 1990Massachusetts Institute Of TechnologyMicrocapsules of polysaccharide core and ionically interacting skin, polysaccharide-degrading enzyme
US4942129 *Jul 12, 1988Jul 17, 1990Queen's University At KingstonCore of living tissue such as hybridoma or insect cells, a double polymer membranes to make a microcapsule
US4954443 *Nov 18, 1988Sep 4, 1990The Nisshin Oil Mills, Ltd.Method of immobilizing biochemically active substance with xanthan gum
US4956128 *Nov 13, 1986Sep 11, 1990Connaught Laboratories LimitedMicroencapsulation
US4962047 *Oct 28, 1986Oct 9, 1990Intracel CorporationMixing and separating solid phase supports by pressure variation
US4971833 *Nov 2, 1987Nov 20, 1990Excorim KbMethod of coating solid particles with a hydrophilic gel
US5021350 *Jun 8, 1989Jun 4, 1991Rhone-Poulenc IndustriesEmbedding a liquid mycelium culture in a polysaccharide gel and storing
US5026365 *Apr 29, 1987Jun 25, 1991The University Of MassachusettsMethod and apparatus for therapeutically treating immunological disorders and disease states
US5055402 *Jan 4, 1989Oct 8, 1991Bio-Recovery Systems, Inc.Removal of metal ions with immobilized metal ion-binding microorganisms
US5070019 *Mar 7, 1990Dec 3, 1991Huels AktiengesellschaftSodium alginate and calcium chloride
US5084350 *Feb 16, 1990Jan 28, 1992The Royal Institution For The Advance Of Learning (Mcgill University)Reversible gelation, nonagglomerating
US5093253 *Jul 2, 1990Mar 3, 1992Monsanto CompanyMethod for microbial immobilization by entrapment in gellan gum
US5101814 *Aug 11, 1989Apr 7, 1992Palti Yoram ProfSystem for monitoring and controlling blood glucose
US5106627 *Nov 14, 1990Apr 21, 1992Brown University Research FoundationFor controlled delivery of encapsulated neurotransmitter to brain; growth factor source
US5116747 *Aug 11, 1989May 26, 1992University Of WaterlooImmobilization of biologically active material in capsules prepared from a water-soluble polymer and chitosan acetate
US5139783 *Apr 9, 1990Aug 18, 1992L'orealSlowly introducing aqueous alginate solution through nozzle into crosslinking solution of polyvalent metal salt
US5149543 *Oct 5, 1990Sep 22, 1992Massachusetts Institute Of TechnologyIonically cross-linked polymeric microcapsules
US5156844 *Feb 26, 1992Oct 20, 1992Brown University Research FoundationFor controlled delivery of a neurotransmitter to the brain
US5158881 *Jan 8, 1990Oct 27, 1992Brown University Research FoundationMethod and system for encapsulating cells in a tubular extrudate in separate cell compartments
US5167811 *Mar 4, 1992Dec 1, 1992Trustees Of The University Of PennsylvaniaExterior coating binds with biomaterial
US5167812 *Jan 17, 1992Dec 1, 1992Trustees Of The Univ. Of Penna.Affinity chromatogry using dried calcium alginate-magnetite separation media in a magnetically stabilized fluidized bed
US5170744 *Dec 13, 1991Dec 15, 1992Biosys CorporationUsing phanran or xanthan gum
US5175093 *Nov 7, 1989Dec 29, 1992Lehigh UniversityBioactive cells immobilized in alginate beads containing voids formed with polyethylene glycol
US5182111 *Jun 28, 1991Jan 26, 1993Boston University Research FoundationIn vivo delivery of active factors by co-cultured cell implants
US5190041 *Dec 27, 1991Mar 2, 1993Palti Yoram ProfSystem for monitoring and controlling blood glucose
US5204111 *Jan 28, 1992Apr 20, 1993L'orealProcess for the preparation of alginate capsules, apparatus for producing said capsules and cosmetic compositions containing said capsules
US5227298 *Aug 17, 1990Jul 13, 1993The Trustees Of Columbia University In The City Of New YorkDouble-walled bead, pancreatic islet transplantation, discordant xenografts
US5232712 *Jun 28, 1991Aug 3, 1993Brown University Research FoundationExtrusion apparatus and systems
US5260002 *Dec 23, 1991Nov 9, 1993Vanderbilt UniversityMethod and apparatus for producing uniform polymeric spheres
US5264359 *Apr 13, 1989Nov 23, 1993Nitta Gelatin Inc.Suspension in collagen then expelling and coating with alginates, hardening and warming the coated solution for gelation and embedding
US5279745 *Dec 26, 1991Jan 18, 1994The United States Of America As Represented By The Secretary Of The InteriorPolysulfones impregnated with powdered activated carbo
US5283187 *Jan 8, 1991Feb 1, 1994Brown University Research FoundationCell culture-containing tubular capsule produced by co-extrusion
US5292657 *Feb 26, 1992Mar 8, 1994Pioneer Hi-Bred International, Inc.Process for preparing rotary disc fatty acid microspheres of microorganisms
US5308701 *May 8, 1992May 3, 1994Smadar CohenEncapsulation biological material
US5314471 *Apr 1, 1992May 24, 1994Baxter International Inc.Tissue inplant systems and methods for sustaining viable high cell densities within a host
US5334640 *Apr 8, 1992Aug 2, 1994Clover Consolidated, Ltd.Ionically covalently crosslinked and crosslinkable biocompatible encapsulation compositions and methods
US5344454 *Apr 1, 1992Sep 6, 1994Baxter International Inc.Closed porous chambers for implanting tissue in a host
US5368028 *Jun 16, 1993Nov 29, 1994Cb-Carmel Biotechnology Ltd.System for monitoring and controlling blood and tissue constituent levels
US5380536 *Aug 5, 1991Jan 10, 1995The Board Of Regents, The University Of Texas SystemBiocompatible microcapsules
US5385741 *Feb 25, 1992Jan 31, 1995Champagne Moet & ChandonReducing calcium ion content of calcium alginate gel by contacting with aqueous solution of acid
US5387522 *Jul 22, 1991Feb 7, 1995Schering CorporationApparatus having a biphasic spray head for entrapping biological material in a hydrophilic gel
US5389535 *Dec 17, 1993Feb 14, 1995Brown University Research FoundationMethod of encapsulating cells in a tubular extrudate
US5401516 *Apr 22, 1993Mar 28, 1995Emisphere Technologies, Inc.Encapsulation of biologically active materials, drug delivery, reaction with benzenesulfonyl chloride or benzoyl chloride
US5410016 *Mar 1, 1993Apr 25, 1995Board Of Regents, The University Of Texas SystemA curable additional polymerizable macromolecular monomers comprising at least one water soluble region, at least one degradable, hydrolyzable region and free radical polymerizable end groups; drug delivery
US5418154 *Dec 24, 1992May 23, 1995Brown University Research FoundationMethod of preparing elongated seamless capsules containing biological material
US5427935 *Jun 29, 1993Jun 27, 1995The Regents Of The University Of MichiganHybrid membrane bead and process for encapsulating materials in semi-permeable hybrid membranes
US5429821 *May 29, 1992Jul 4, 1995The Regents Of The University Of CaliforniaNon-fibrogenic high mannuronate alginate coated transplants, processes for their manufacture, and methods for their use
US5441878 *Dec 8, 1987Aug 15, 1995Thies Technology, Inc.Preparation of uniform droplets by using gas pressure to force liquid from a syringe and flowing gas to detach droplets
US5447728 *Dec 16, 1993Sep 5, 1995Emisphere Technologies, Inc.A carrier comprising an acylated amino acid; lowering iron concentration in mammals
US5451410 *Apr 22, 1993Sep 19, 1995Emisphere Technologies, Inc.Modified amino acids for encapsulating active agents
US5453270 *Mar 2, 1993Sep 26, 1995Hypermetabolic Therapies, Inc.Pharmaceutical composition and method for hypermetabolic weight loss
US5453368 *Aug 27, 1993Sep 26, 1995Brown University Research FoundationMethod of encapsulating biological substances in microspheres
US5459054 *Jul 2, 1993Oct 17, 1995Neocrin CompanyCells encapsulated in alginate containing a high content of a- l- guluronic acid
US5459258 *Mar 1, 1994Oct 17, 1995Massachusetts Institute Of TechnologyStarches
US5462866 *Sep 23, 1993Oct 31, 1995Vanderbilt UniversitySemipermeable microspheres encapsulating biological material
US5462990 *Oct 5, 1993Oct 31, 1995Board Of Regents, The University Of Texas SystemBlock copolymers with a non-binding polynonionic component and a water soluble polycationic portion for tissue binding; useful in inhibiting post-surgical adhesions
US5470731 *Jun 8, 1994Nov 28, 1995The Regents Of The University Of CaliforniaCoated transplant and method for making same
US5484721 *Oct 18, 1991Jan 16, 1996Lvmh RechercheEncapsulation of microorganisms for wine making
US5487390 *Jan 14, 1994Jan 30, 1996Massachusetts Institute Of TechnologyGas-filled polymeric microbubbles for ultrasound imaging
US5487739 *Jun 2, 1995Jan 30, 1996Brown University Research FoundationImplantable therapy systems and methods
US5494682 *Mar 18, 1994Feb 27, 1996Massachusetts Institute Of TechnologyEncapsulated biomass in crosslinked polymer material
US5500161 *Sep 21, 1993Mar 19, 1996Massachusetts Institute Of Technology And Virus Research InstituteProtein drug delivery
US5514377 *Mar 8, 1994May 7, 1996The Regents Of The University Of CaliforniaIn situ dissolution of alginate coatings of biological tissue transplants
US5521079 *Jan 24, 1994May 28, 1996The Regents Of The University Of CaliforniaMicrocapsule generating system containing an air knife and method of encapsulating
US5531735 *Sep 27, 1994Jul 2, 1996Hercules IncorporatedMedical devices containing triggerable disintegration agents
US5531997 *Jun 5, 1995Jul 2, 1996The Regents Of University Of CaliforniaTransplant with coating of immunological multilayer barrier membrane of gellable polymer and cationic amino acid polymer
US5540939 *Apr 25, 1994Jul 30, 1996Emisphere Technologies, Inc.Encapsulating active materials
US5541155 *Apr 22, 1994Jul 30, 1996Emisphere Technologies, Inc.Acids and acid salts and their use in delivery systems
US5545223 *Mar 30, 1995Aug 13, 1996Baxter International, Inc.Ported tissue implant systems and methods of using same
US5545423 *Mar 6, 1995Aug 13, 1996Vivorx, Inc.Cytoprotective, biocompatible, retrievable macrocapsule containment systems for biologically active materials
US5550050 *Apr 15, 1994Aug 27, 1996Cytotherapeutics, Inc.Exposing cells enclosed in biocompatible capsules to restrictive environmental conditions which match those which will be encountered after implantation until desired responses are established
US5550178 *Jun 13, 1994Aug 27, 1996Vivorx, Inc.Process for encapsulating biologics using crosslinkable biocompatible encapsulation system
US5554148 *May 26, 1995Sep 10, 1996Brown University Research FoundationRenewable neural implant device and method
US5562099 *Aug 18, 1994Oct 8, 1996Massachusetts Institute Of TechnologyPolymeric microparticles containing agents for imaging
US5567435 *Jun 6, 1995Oct 22, 1996Board Of Regents, The University Of Texas SystemMixing active material with a solution of polymerizable macromer comprising degradable region and free radical polymerizable end groups
US5567440 *Jun 6, 1995Oct 22, 1996Board Of Regents, The University Of Texas SystemMethods for modifying cell contact with a surface
US5567451 *Jan 4, 1995Oct 22, 1996Champagne Moet & ChandonAlginate or pectate gel deficient in gelling ions for use in binding metal ions
US5567612 *Jul 27, 1993Oct 22, 1996Massachusetts Institute Of TechnologyPolymeric matrix provides scaffolding for cell attachment
US5569462 *Mar 31, 1995Oct 29, 1996Baxter International Inc.Placing a population of therapeutic substance producing cells into cell receiving chamber of immunoisolation apparatus, implanting apparatus into patient, administering an immunomodulatory agent
US5578314 *Jan 24, 1994Nov 26, 1996The Regents Of The University Of CaliforniaMultiple layer alginate coatings of biological tissue for transplantation
US5578323 *Jun 14, 1993Nov 26, 1996Emisphere Technologies, Inc.Proteinoid carriers and methods for preparation and use thereof
US5578547 *May 26, 1994Nov 26, 1996Aero-Terra-Aqua Technologies Corp.Peat moss, sodium silicate or polysulfone binder
US5585183 *Apr 13, 1994Dec 17, 1996National Science CouncilPreparation of liquid-core microcapsules for cell cultures
US5593440 *May 23, 1994Jan 14, 1997Baxter International Inc.Tissue implant systems and methods for sustaining viable high cell densities within a host
US5601846 *May 9, 1995Feb 11, 1997Emisphere Technologies, Inc.Oligopeptide
US5602071 *May 17, 1995Feb 11, 1997Aero-Terra-Aqua Technologies CorporationComprising peat moss and a poly(carboxylic acid) binder that has been crosslinked and neutralized with an alkali metal; sorption
US5620883 *Apr 1, 1994Apr 15, 1997The Johns Hopkins UniversityActive cell enclosure having biopolymeric inner layer of cationic modified collagen or anionic hyaluronic acid(esterified or treated with amine) and outer layer of synthetic polyelectrolyte with opposite charge
US5624839 *May 30, 1995Apr 29, 1997Seikagaku Kogyo Kabushiki Kaisha (Seikagaku Corporation)Process for culturing hepatocytes for formation of spheroids
US5626863 *Jan 27, 1995May 6, 1997Board Of Regents, The University Of Texas SystemPhotopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers
US5629020 *Apr 22, 1994May 13, 1997Emisphere Technologies, Inc.Delivery of sensitive agents such as bioactive peptides
US5629187 *Jun 7, 1995May 13, 1997Lvmh RechercheAlginates
US5635609 *Apr 13, 1994Jun 3, 1997ColeticaHaving stable membrane encapsulating particle core; cosmetics, drugs, reagents
US5639275 *May 25, 1995Jun 17, 1997Cytotherapeutics, Inc.Capsule containing genetically engineered cells
US5639467 *Apr 14, 1995Jun 17, 1997The Regents Of The University Of CaliforniaElectrostatic process for manufacturing coated transplants and product
US5643569 *Jun 7, 1995Jul 1, 1997The Rogosin InstitutePreparation of agarose coated, solid agarose-collagen beads containing secretory cells
US5643594 *May 3, 1994Jul 1, 1997The Regents Of The University Of CaliforniaForming microcapsules of biological tissue coated with crosslinked alginates, projecting beads from a rotating cup and collecting them in an independently rotating container of gelling solution
US5643773 *Apr 27, 1995Jul 1, 1997Brown University Research FoundationPreparation of elongated seamless capsules containing a coaxial rod and biological material
US5643957 *Oct 25, 1994Jul 1, 1997Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US5650386 *Mar 31, 1995Jul 22, 1997Emisphere Technologies, Inc.Compositions for oral delivery of active agents
US5651980 *Apr 15, 1994Jul 29, 1997Biohybrid Technologies, Inc.Methods of use of uncoated gel particles
US5653687 *Jun 6, 1995Aug 5, 1997Brown University Research FoundationMethod and apparatus for sealing implantable, membrane encapsulation
US5653688 *Jun 6, 1995Aug 5, 1997Brown University Research FoundationMethod and apparatus for sealing implantable membrane encapsulation devices
US5653756 *Sep 2, 1994Aug 5, 1997Baxter International Inc.Closed porous chambers for implanting tissue in a host
US5653975 *May 25, 1995Aug 5, 1997Cytotherapeutics, Inc.Implanting encapsulated cells capable of producing human growth factor or trophic factor for diffusion into the central nervous system; treatment of diabetes; anemia; hypoparathyroidism; parkinson's and alzheimer's disease
US5656469 *Aug 14, 1995Aug 12, 1997Brown University Research FoundationMaintaining coating-forming liquid film sheet transverse to vertical plane, causing drops of biological substances in aqueous medium to fall downwardly through liquid film to form microcapsules, polymerizing to make self-supporting
US5656481 *May 25, 1995Aug 12, 1997Cyto Therapeutics, Inc.Compositions and methods for the delivery of biologically active molecules using cells contained in biocompatible capsules
US5660630 *Mar 30, 1995Aug 26, 1997Yazaki CorporationSeedlike substance making apparatus
US5667806 *Jun 7, 1995Sep 16, 1997Emisphere Technologies, Inc.Spray drying method and apparatus
US5676924 *Dec 17, 1993Oct 14, 1997Rhode Island HospitalIn vivo assay to determine cancer treatment effectiveness
US5676943 *May 25, 1995Oct 14, 1997Cytotherapeutics, Inc.Nerve growth factor
US5693338 *Sep 29, 1994Dec 2, 1997Emisphere Technologies, Inc.Delivery composition comprising active agent, diketopiperazine, enzyme inhibitor
US5693514 *Sep 2, 1994Dec 2, 1997The Regents Of The Univesity Of CaliforniaNon-fibrogenic high mannuronate alginate coated transplants, processes for their manufacture, and methods for their use
US5698413 *May 5, 1993Dec 16, 1997The United States Of America As Represented By The Department Of Health And Human ServicesMethod of evaluating chemotherapeutic agents in vivo
US5709854 *Apr 30, 1993Jan 20, 1998Massachusetts Institute Of TechnologyTissue formation by injecting a cell-polymeric solution that gels in vivo
US5709861 *Jan 13, 1995Jan 20, 1998Emisphere Technologies, Inc.Compositions for the delivery of antigens
US5712161 *Dec 26, 1994Jan 27, 1998Nitta Gelatin Inc.Collagen
US5713887 *Jun 6, 1995Feb 3, 1998Brown University Research FoundationMethod and apparatus for sealing implantable, membrane encapsulation devices
US5713888 *Jun 5, 1995Feb 3, 1998Baxter International, Inc.Tissue implant systems
US5714167 *Oct 25, 1994Feb 3, 1998Emisphere Technologies, Inc.Reversibly forming supramolecular complex of active agent with perturbant; drug delivery
US5716404 *Dec 16, 1994Feb 10, 1998Massachusetts Institute Of TechnologyBreast tissue engineering
US5733336 *Mar 30, 1995Mar 31, 1998Baxter International, Inc.Ported tissue implant systems and methods of using same
US5736371 *May 16, 1994Apr 7, 1998A Et S BiovecteursBiodegradable particulate vector for transporting molecules having biological activity
US5738673 *Jun 7, 1995Apr 14, 1998Brown University Research FoundationFor biological material; biocompatibility, drug delivery
US5738876 *Sep 20, 1996Apr 14, 1998Metabolex, Inc.Method of solution overcoating with gelling polymer
US5741330 *Jun 7, 1995Apr 21, 1998Baxter International, Inc.Close vascularization implant material
US5741685 *Jun 7, 1995Apr 21, 1998Children's Medical Center CorporationParenchymal cells packaged in immunoprotective tissue for implantation
US5759578 *May 23, 1996Jun 2, 1998Vivorx, Inc.Insulin drug delivery; diabetes
US5762959 *May 28, 1993Jun 9, 1998Vivorx, Inc.Testing for explosion, implosion, diffusion, swelling and end product secretion; useful for cell grafting
US5766633 *Apr 22, 1994Jun 16, 1998Emisphere Technologies, Inc.Modified amino acid carrier, bioactive peptides
US5782912 *Mar 17, 1994Jul 21, 1998Baxter International, Inc.Close vascularization implant material
US5792451 *Mar 2, 1994Aug 11, 1998Emisphere Technologies, Inc.Oral drug delivery compositions and methods
US5795570 *Apr 7, 1995Aug 18, 1998Emory UniversityMethod of containing core material in microcapsules
US5798113 *May 24, 1995Aug 25, 1998Brown University Research FoundationGrafting a vehicle containing core which contains isolated cells, either suspended in liquid or immobilized within hydrogel matrix, surrounded by a biocompatible jacket which protects isolated cells in core from immunological attack
US5800529 *Jun 7, 1995Sep 1, 1998Baxter International, Inc.Close vascularization implant material
US5800828 *Jan 10, 1994Sep 1, 1998Brown University Research FoundationImplantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5800829 *May 24, 1995Sep 1, 1998Brown University Research FoundationMethods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US5804178 *Feb 28, 1994Sep 8, 1998Massachusetts Institute Of TechnologyImplantation of cell-matrix structure adjacent mesentery, omentum or peritoneum tissue
US5804688 *Feb 7, 1997Sep 8, 1998Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US5820881 *Apr 28, 1995Oct 13, 1998Emisphere Technologies, Inc.Microspheres of diamide-dicarboxylic acids
US5820882 *Nov 10, 1994Oct 13, 1998Board Of Regents, The University Of Texas SystemBiocompatible microcapsules
US5824345 *Jun 7, 1995Oct 20, 1998Emisphere Technologies, Inc.Microsphere comprising active agent, proteinoid, modified hydrolyzed vegetable protein
US5827707 *Jun 7, 1995Oct 27, 1998Neocrin CompanyMethod for manufacturing minimal volume capsules containing biological materials
US5834001 *May 24, 1995Nov 10, 1998Brown University Research FoundationMethods for making immunoisolatory implantable vehicles with a biocompatiable jacket and a biocompatible matrix core
US5834274 *Jun 6, 1995Nov 10, 1998Board Of Regents, The University Of Texas SystemFree radical photopolymerizable
US5840340 *Aug 30, 1996Nov 24, 1998Emisphere Technologies, Inc.Oligopeptides with fragrance, cosmetics and dye
US5851833 *Aug 7, 1996Dec 22, 1998Children's Medical Center Corp.Neomorphogenesis of urological structures in vivo from cell culture
US5855610 *May 19, 1995Jan 5, 1999Children's Medical Center CorporationEngineering of strong, pliable tissues
US5858746 *Jan 25, 1995Jan 12, 1999Board Of Regents, The University Of Texas SystemAddition polymerization of a water-soluble macromolecular monamer to coat, support, microencapsulate, plug, adhere cells, cell aggregates or tissue
US5863715 *Jan 11, 1996Jan 26, 1999The Governors Of The University Of AlbertaMethods for bulk cryopreservation encapsulated islets
US5863944 *Apr 30, 1997Jan 26, 1999Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US5866536 *Feb 6, 1997Feb 2, 1999Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US5869077 *May 24, 1995Feb 9, 1999Brown University Research FoundationSubcutaneously implanting in patient immunoisolatory vehicle comprising core containing living cells which secrete insulin dispersed in biocompatible matrix, surrounded by biocompatible external permselective jacket
US5871767 *May 24, 1995Feb 16, 1999Brown University Research FoundationImplanting in patient immunoisolatory vehicle comprising core containing living cells which secrete biologically active material dispersed in biocompatible matrix, surrounded by biocompatible external jacket
US5872279 *Mar 19, 1998Feb 16, 1999Nippon Chemical Industrial Co., Ltd.Bis(1,1,3,3-tetramethylbutyl) phosphinic acid compound, a production method thereof and an extracting agent
US5874099 *May 24, 1995Feb 23, 1999Brown University Research FoundationMethods for making immunoisolatary implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US5876710 *Feb 7, 1997Mar 2, 1999Emisphere Technologies Inc.Drug delivery; using a brominated benzamide compound
US5876742 *Nov 26, 1996Mar 2, 1999The Regents Of The University Of CaliforniaBiological tissue transplant coated with stabilized multilayer alginate coating suitable for transplantation and method of preparation thereof
US5879681 *Feb 7, 1997Mar 9, 1999Emisphere Technolgies Inc.Compounds and compositions for delivering active agents
US5879709 *May 11, 1998Mar 9, 1999Vivorx, Inc.Method of treating patients with diabetes
US5882354 *Jun 7, 1995Mar 16, 1999Baxter International Inc.Close vascularization implant material
US5888497 *Nov 7, 1996Mar 30, 1999The Rogosin InstituteEncapsulated cells
US5906828 *Oct 8, 1997May 25, 1999Massachusetts Institute Of TechnologyCell growth substrates with tethered cell growth effector molecules
US5906934 *Mar 14, 1995May 25, 1999Morphogen Pharmaceuticals, Inc.Mesenchymal stem cells for cartilage repair
US5908623 *May 25, 1995Jun 1, 1999Cytotherapeutics, Inc.Compositions and methods for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US5912005 *Nov 19, 1996Jun 15, 1999Biohybrid Technologies, Inc.Methods of use of uncoated gel particles
US5916554 *Jun 5, 1995Jun 29, 1999Washington UniversityInsulin
US5916790 *Mar 3, 1995Jun 29, 1999Metabolex, Inc.Encapsulation compositions, and methods
US5919702 *Oct 23, 1996Jul 6, 1999Advanced Tissue Science, Inc.Collecting wharton's jelly from umbilical cords, culturing so that pre-chondrocytes proliferate, isolating pre-chondrocytes which give rise to chondrocytes which produce cartilage tissue for therapeutic use
US5932460 *Jun 6, 1995Aug 3, 1999Brown University Research FoundationMethod and apparatus for sealing implantable, membrane encapsulation devices containing living cells
US5939381 *Feb 7, 1997Aug 17, 1999Emisphere Technologies, Inc.4-(4-(phenoxyacetyl)aminophenyl)butyric acid as a carrier for drug delivery
US5945100 *Jul 31, 1996Aug 31, 1999Fbp CorporationTumor delivery vehicles
US5955503 *Feb 6, 1997Sep 21, 1999Emisphere Technologies, Inc.Modified amino acid compounds useful as carriers in the delivery of biologically active agents such as, for example, bioactive peptides and the like
US5958457 *May 10, 1995Sep 28, 1999Emisphere Technologies, Inc.Compositions for the delivery of antigens
US5962710 *May 9, 1997Oct 5, 1999Emisphere Technologies, Inc.Reacting an oligosalicylate and an amino acid
US5964804 *Jun 7, 1995Oct 12, 1999Baxter International Inc.Close vascularization implant material
US5965121 *Feb 6, 1997Oct 12, 1999Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US5965149 *Feb 14, 1994Oct 12, 1999Thermo Trilogy CorporationGranular formulation of biological entities with improved storage stability
US5968794 *Jan 23, 1998Oct 19, 1999Biovector Therapeutics S.A.Cross-linked polysaccharide or oligosaccharide matrix having grafted, uniformly distributed ionic ligands; particle sizes range from 10 nanometers to 10 micrometers; for encapsulation of active materials
US5972387 *Nov 21, 1994Oct 26, 1999Emisphere Technologies, Inc.Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof
US5976569 *Apr 29, 1997Nov 2, 1999Emisphere Technologies, Inc.Diketopiperazine-based delivery systems
US5976780 *Jun 2, 1998Nov 2, 1999Shah; Kumarpal A.Encapsulated cell device
US5985309 *Nov 17, 1997Nov 16, 1999Massachusetts Institute Of TechnologyPreparation of particles for inhalation
US5989539 *Feb 6, 1997Nov 23, 1999Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US5990166 *Feb 7, 1997Nov 23, 1999Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US6001347 *Feb 6, 1997Dec 14, 1999Emisphere Technologies, Inc.Organic acid compound of given structure having an aromatic amide group, a methoxy group in the ortho position on the aromatic ring, and a lipophilic chain terminated with a carboxylic acid is useful as a nontoxic carrier
US6001387 *Jul 1, 1997Dec 14, 1999The Reguents Of The University Of CaliforniaSpin disk encapsulation apparatus and method of use
US6020200 *Mar 1, 1996Feb 1, 2000Metabolex, Inc.Encapsulation compositions and methods
US6023009 *Oct 24, 1997Feb 8, 2000Circe Biomedical, Inc.Pancreatic islet cells capable of producing insulin, encapsulated within a semipermeable spheroidal membrane comprising agar gel.
US6033888 *Jul 10, 1997Mar 7, 2000University Of FloridaProcess for microencapsulating cells
US6045818 *Nov 25, 1998Apr 4, 2000Massachusetts Institute Of TechnologyCell growth substrates with tethered cell growth effector molecules
US6051258 *Jun 7, 1995Apr 18, 2000Emisphere Technologies, Inc.Proteinoid emulsions and methods for preparation and use thereof
US6060513 *Feb 7, 1997May 9, 2000Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US6060582 *Aug 4, 1998May 9, 2000The Board Of Regents, The University Of Texas SystemPhotopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers
US6071510 *Apr 23, 1997Jun 6, 2000Emisphere Technologies, Inc.Modified amino acids and compositions comprising the same for delivering active agents
US6071538 *Sep 30, 1997Jun 6, 2000Emisphere Technologies, Inc.Oral delivery composition comprising supramolecular complex
US6083523 *Sep 4, 1998Jul 4, 2000Brown University Research FoundationImplantable biocompatable immunoisolatory vehicle for delivery of selected therapeutic products
US6084112 *Sep 10, 1996Jul 4, 2000Emisphere Technologies, Inc.Method for preparing ω-aminoalkanoic acid derivatives from cycloalkanones
US6090958 *Feb 7, 1997Jul 18, 2000Emisphere Technologies, Inc.N-(8-carboxyoctyl)-o-hydroxybenzamide and salts
US6096303 *Jul 31, 1997Aug 1, 2000Medical College Of Georgia Research Institute, Inc.Method to enhance treatment of cystic tumors
US6099856 *Dec 10, 1996Aug 8, 2000Emisphere Technologies, Inc.Increased bioavailable
US6100285 *Nov 11, 1997Aug 8, 2000Emisphere Technologies, Inc.Method of solubilizing itraconazole
US6100298 *Feb 6, 1997Aug 8, 2000Emisphere Technologies, Inc.Mixture of drug and n-(4-(carboxypropyl)phenyl-4-phenyl-butyramide for improved oral drug delivery
US6123700 *Jan 30, 1998Sep 26, 2000Brown University Research FoundationMethod and apparatus for sealing implantable membrane encapsulation devices
US6129761 *Jun 7, 1995Oct 10, 2000Reprogenesis, Inc.Mixing dissociated cells with solution comprising biocompatible hyaluronic acid, alginate polymer capable of crosslinking to form hydrogel, forming suspension, implanting into animal, crosslinking to form hydrogel matrix
US6136295 *Dec 15, 1998Oct 24, 2000Massachusetts Institute Of TechnologyBiocompatible particles for delivery of a therapeutic, prophylactic or diagnostic agent to the pulmonary system comprising a therapeutic, prophylactic or diagnostic agent
US6156305 *Jun 5, 1995Dec 5, 2000Baxter International Inc.Implanted tumor cells for the prevention and treatment of cancer
US6165503 *Jul 1, 1998Dec 26, 2000Fmc Biopolymer A.S.Preparing gelled beads of a polyanionic polysaccharide which are cross-linked with a polyvalent cation, forming capsules having polycationic-polyanion membrane of polycationic polysaccharide on gelled beads, culturing the product capsule
US6174299Dec 4, 1998Jan 16, 2001Harvey B. PollardMethod for treating hemophilia A and B and AIDS and devices used therein
US6179826Oct 29, 1996Jan 30, 2001Brown University Research FoundationImplantable therapy systems and methods
US6180140Jun 2, 1995Jan 30, 2001Emisphere Technologies, Inc.Modified amino acids for drug delivery
US6193988Jul 12, 1996Feb 27, 2001Stoner, Ii Richard J.For controlling disease in growing plants
US6194191Nov 20, 1997Feb 27, 2001Introgen Therapeutics, Inc.Method for the production and purification of adenoviral vectors
US6221367Sep 29, 1997Apr 24, 2001Emisphere Technologies, Inc.Exposing a biologically active agent to a complexing perturbant to reversibly transform the biologically active agent to the intermediate state and to form a transportable supramolecular complex
US6224912Nov 9, 1998May 1, 2001The Rogo InstituteCancer-cell proliferation-suppressing material produced by cancer cells restricted by entrapment
US6231892Nov 13, 1997May 15, 2001The Board Of Regents, The University Of Texas SystemCompositions for coating microcapsules and other surfaces
US6242495Jun 16, 2000Jun 5, 2001Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US6245359Sep 30, 1997Jun 12, 2001Emisphere Technologies, Inc.Active agent transport systems
US6248321 *Jan 14, 1999Jun 19, 2001Her Majesty The Queen In Right Of Canada, As Represented By The Minister Of Natural Resources, Canadian Forestry ServiceEncapsulation of microparticles in teardrop shaped polymer capsules of cellular size
US6258870Jan 13, 1997Jul 10, 2001Board Of Regents, The University Of Texas SystemsGels for encapsulation of biological materials
US6264941Jan 25, 1999Jul 24, 2001Neurotech S.A.Compositions for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US6281015Dec 16, 1994Aug 28, 2001Children's Medical Center Corp.Introducing a microsphere with a bioactive factor to a hepatocyte seeded biodegradable polymer matrix into a transplantation site; enhancing survival and proliferation of transplanted cells
US6303355Mar 22, 1999Oct 16, 2001Duke UniversityMethod of culturing, cryopreserving and encapsulating pancreatic islet cells
US6306922Jan 26, 2000Oct 23, 2001Boards Of Regents, The University Of Texas SystemMacromer polymers crosslinked by photopolymerization
US6313088Feb 7, 1997Nov 6, 2001Emisphere Technologies, Inc.Carriers used to deliver various active agents through various biological, chemical, and physical barriers
US6322804May 2, 2000Nov 27, 2001Neurotech S.A.Implantable biocompatible immunoisolatory vehicle for the delivery of selected therapeutic products
US6331318Sep 30, 1994Dec 18, 2001Emisphere Technologies Inc.Carbon-substituted diketopiperazine delivery systems
US6340594Dec 5, 1997Jan 22, 2002Cellfor, Inc.Production of desiccation-tolerant gymnosperm embryos
US6346242Feb 8, 2000Feb 12, 2002Emishpere Technologies, Inc.Compounds and compositions for delivering active agents
US6348069Nov 3, 1998Feb 19, 2002Children's Medical Center CorporationEngineering of strong, pliable tissues
US6348207Sep 30, 1997Feb 19, 2002Emisiphere Technologies, Inc.Exposing biologically active agent to complexing perturbant to reversibly transform biologically active agent to intermediate state and form orally deliverable supramolecular complex, orally administering complex to subject
US6365385Dec 1, 1999Apr 2, 2002Duke UniversityCulturing with antioxidant, anticytokine, antiendotoxin and antibiotic; microencapsulating in biocompatible structure having core and semipermeable outer membrane; then incubating in physiological salt to increase capsule durability
US6368612Dec 24, 1997Apr 9, 2002Biohybrid Technologies LlcInsertable device
US6372496Dec 5, 1997Apr 16, 2002Cellfor, Inc.Mature viable gymnosperm somatic embryo
US6375983Jun 12, 1997Apr 23, 2002Emisphere Technologies, Inc.Microencapsulated fragrances and method for preparation
US6395678Sep 1, 1999May 28, 2002Aero-Terra-Aqua Technologies CorporationActivated carbon in binder; water pollution control
US6399102May 1, 2000Jun 4, 2002The Penn State Research FoundationAerodynamically light particles for pulmonary drug delivery
US6413550Nov 23, 1998Jul 2, 2002Emisphere Technologies, Inc.Proteinoid carriers and methods for preparation and use thereof
US6428780May 5, 1999Aug 6, 2002Emisphere Technologies, Inc.Modified amino acid
US6443941 *Jul 24, 2000Sep 3, 2002Endoluminal Therapeutics, Inc.Introducing polycaprolactone pliable tube containing living cells into lumen of diseased organ; chemical or physical reconfiguration to mold polymer to wall of cavity; preventing abrupt reclosure or restenosis postangioplasty
US6461545Jan 6, 2000Oct 8, 2002Emisphere Technologies, Inc.Method of solubilizing and encapsulating itraconazole
US6461641Feb 3, 1999Oct 8, 2002Fbp CorporationAdding to bioactive agent polymeric vehicle which gels or solidifies at time of or shortly after injection and has consistency and density to displace cells and to retain bioactive agent at injection site, thereby enhancing delivery
US6495161 *Mar 9, 1999Dec 17, 2002Vivorx, Inc.Capsules containing such as islet of langerhans, hepatocytes, lymphocytes used for drugs or medical diagnosis, having strength, permeability, porosity and time release
US6528165Mar 25, 2002Mar 4, 2003Luminex CorporationEncapsulation of discrete quanta of fluorescent particles
US6531156Jul 12, 1999Mar 11, 2003Temple UniversityAqueous solven encapsulation method, apparatus and microcapsules
US6602975Oct 22, 2001Aug 5, 2003Board Of Regents, The University Of Texas SystemPhotopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers
US6632446Oct 23, 2000Oct 14, 2003The Board Of Regents, University Of Texas SystemBiocompatible substrates; free radical polymerization initiator; crosslinked networks of water soluble polymers; acrylated polyethylene glycol; microencapsulation
US6635283Dec 20, 2001Oct 21, 2003Penn State Res FoundBiocompatible particles having therapeutic, prophylactic or diagnostic agent, and of given mass mean diameter and aerodynamic diameter; at least 46% of the mass of particles are deposited after the first bifurcation of the lungs
US6649384Jul 5, 2001Nov 18, 2003Islet Technology, Inc.Using polymer; atomizing, rotation
US6652837Sep 13, 1999Nov 25, 2003Massachusetts Institute Of TechnologyPreparation of novel particles for inhalation
US6656470May 11, 2001Dec 2, 2003Pharmacia & Upjohn CompanyVaccine composition, method of preparing the same, and method of vaccinating vertebrates
US6656508 *Apr 17, 1997Dec 2, 2003Amgen Inc.Sustained-release alginate gels
US6689608Sep 26, 2000Feb 10, 2004Massachusetts Institute Of TechnologyPolymeric matrix formed of biodegradable, biocompatible, synthetic, amorphous or semi-crystalline polymer having specified crystallinity, porosity and pore size, suitable for attachment and proliferation of dissociated cells
US6699272Dec 13, 2001Mar 2, 2004Endoluminal Therapeutics, Inc.Biodegradable polymeric endoluminal sealing process, apparatus and polymeric products for use therein
US6703127Sep 27, 2001Mar 9, 2004Microtek Laboratories, Inc.Macrocapsules containing microencapsulated phase change materials
US6749835Aug 23, 2000Jun 15, 2004Advanced Inhalation Research, Inc.Hydroxy-di- or tricarboxylic acid, phospholipid, inorganic salt and active ingredient; nonagglomerating; avoiding or suspending lung's natural clearance mechanisms until drug delivery is complete; short and long term release
US6773458 *Dec 12, 1994Aug 10, 2004Baxter International Inc.Surgically implant living cells in a host to treat cell and molecular deficiency diseases; pancreatic islets
US6773713Feb 21, 2002Aug 10, 2004University Of MassachusettsProviding a negative mold having a defined shape; suspending isolated tissue precursor cells in a hydrogel, introducing suspension into the mold, inducing gelation to solidify liquid hydrogel-precursor cell to form living tissue
US6783964Jan 23, 2002Aug 31, 2004Duke UniversityMicroencapsulated pancreatic islet cells
US6808705Jan 3, 2003Oct 26, 2004The Rogosin InstituteFor suppressing the proliferation of cancer cells
US6818230Jan 3, 2003Nov 16, 2004The Rogosin InstituteAntiproliferative effect can be achieved by subjecting conditioned medium obtained by culturing the structures of the invention in culture medium to filtration; anticancer agents
US6835334Mar 8, 2004Dec 28, 2004Microtek Laboratories, Inc.Suspending microcapsules in a gelling agent solution, adding as discrete drops to a crosslinking solution, forming macrocapsules and drying
US6840962Sep 25, 2000Jan 11, 2005Massachusetts Institute Of TechnologyTissue engineered tendons and ligaments
US6843922May 7, 2002Jan 18, 2005Ricura Technologies, LlcBead and process for removing dissolved metal contaminants
US6878543Oct 24, 2000Apr 12, 2005Nsgene SaCultures of GFAP+ nestin+ cells that differentiate to neurons
US6905766Jan 31, 2003Jun 14, 2005Luminex CorporationEncapsulation of discrete quanta of fluorescent particles
US6933326Jun 18, 1999Aug 23, 2005Lifecell Coporationfracturing collagen-containing tissue that is acellular and dehydrated and has a basement membrane to which, after rehydration, viable endothelial and epithelial cells attach
US6942868May 20, 2003Sep 13, 2005Massachusetts Institute Of TechnologyAerodynamically light particles for pulmonary drug delivery
US6956021Aug 25, 1999Oct 18, 2005Advanced Inhalation Research, Inc.Stable spray-dried protein formulations
US6958148Jul 21, 2000Oct 25, 2005Pericor Science, Inc.microparticle comprising active agent and polymer having transglutaminase substrate reactive groups, wherein reactive groups are surface available, and polymer comprises amino acids having at least three contiguous linked glutamines; drug delivery
US6960351Jul 21, 2003Nov 1, 2005Brown University Research FoundationImplantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US6990982Mar 12, 2003Jan 31, 2006Bonutti Ip, LlcMethod for harvesting and processing cells from tissue fragments
US6991652 *Jun 12, 2001Jan 31, 2006Burg Karen J LGelable Viscous fluid has macroporous collagen and cells embedd in, can be injected into body, for cells or tissue grow in and attach to; repairing a defect in breast or nipple of female, or facial, spinal disc, bone; biodegradable, absorbable
US7008634Mar 3, 1995Mar 7, 2006Massachusetts Institute Of Technologyincludes growth factors and extracellular matrix molecules flexibly tethered to a support medium; used to stimulate cell and tissue growth by enhancment of the biological response to the growth factor; liver cells
US7041504Dec 12, 2000May 9, 2006The Rogosin InstituteCancer cell-inhibiting culture medium produced by culturing restricted entrapped cancer cells
US7048908Jul 23, 2002May 23, 2006Advanced Inhalation Research, Inc.Particles for inhalation having sustained release properties
US7052678Mar 7, 2002May 30, 2006Massachusetts Institute Of TechnologyParticles for inhalation having sustained release properties
US7125706Jun 12, 2001Oct 24, 2006Introgen Therapeutics, Inc.Method for the production and purification of adenoviral vectors
US7134437Mar 22, 2002Nov 14, 2006Bonutti Ip, LlcMethod for utilizing human tissue
US7153519Jun 25, 2003Dec 26, 2006Board Of Regents, The University Of Texas SystemImplantable substrate coated with a macromer having free radical polymerizable substituents
US7160544Nov 10, 2003Jan 9, 2007Pharmacia & Upjohn CompanyMethod of vaccinating vertebrates
US7182961Nov 20, 2002Feb 27, 2007Advanced Inhalation Research, Inc.Particulate compositions for pulmonary delivery
US7226617Jan 20, 2004Jun 5, 2007Fudan UniversityThermosensitive and biodegradable microgel and a method for the preparation thereof
US7235391Aug 28, 2001Jun 26, 2007Introgen Therapeutics, Inc.Bulking agents, cryoprotectants and lyoprotectants added for storage stability
US7297331Aug 16, 2004Nov 20, 2007The Rogosin InstituteA conditioned culture medium contains biocompatible, selectively-permeable agarose beads that encapsulate the cancer cells, thus restricting cell growth and producing antiproliferative agents; cancers cells of epithelials, breasts, prostate glands, kidneys, and syncytia
US7299805Jun 6, 2003Nov 27, 2007Marctec, LlcScaffold and method for implanting cells
US7303912Feb 22, 2005Dec 4, 2007Nsgene A/SCultures of GFAP nestin cells that differentiate to neurons
US7358284Jan 20, 2005Apr 15, 2008Lifecell CorporationParticulate acellular tissue matrix
US7384649Dec 5, 2006Jun 10, 2008Advanced Inhalation Research, Inc.Particulate compositions for pulmonary delivery
US7413734Jun 25, 2004Aug 19, 2008Ethicon, IncorporatedTreatment of retinitis pigmentosa with human umbilical cord cells
US7417022Apr 11, 2005Aug 26, 2008Mhr Institutional Partners Iia LpAmino acid for deliverying active materials; bioavailability
US7419808Mar 15, 2005Sep 2, 2008Introgen Therapeutics, Inc.Methods and compositions for the production of adenoviral vectors
US7445930Jul 30, 2004Nov 4, 2008Introgen Therapeutics Inc.Method for the production and purification of adenoviral vectors
US7462200Nov 23, 2005Dec 9, 2008Marctec, LlcMethod for tissue grafting
US7462471Feb 10, 2004Dec 9, 2008Massachusetts Institute Of Technologypolymeric matrix formed of a biodegradable, biocompatible, synthetic, amorphous polymer or semi-crystalline polymer having specific crystallinity, porosity and pore size; suitable for attachment and proliferation of dissociated cells
US7510873Jun 25, 2004Mar 31, 2009Ethicon, IncorporatedPostpartum cells isolated from umbilical cord tissue, and methods of making and using the same
US7510875Dec 27, 2001Mar 31, 2009Introgen Therapuetics, Inc.Methods for producing purified adenoviral vectors
US7524489Jun 25, 2004Apr 28, 2009Ethicon IncorporatedRegeneration and repair of neural tissue using postpartum-derived cells
US7534774Oct 2, 2002May 19, 2009Tissue Repair CompanyContacting a wound site with formulation comprising nucleic acid molecule and a biocompatible matrix, the wound site being situated in a tissue associated with the fluid space
US7553872Feb 13, 2006Jun 30, 2009Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US7560276Jun 25, 2004Jul 14, 2009Ethicon, IncorporatedSoft tissue repair and regeneration using postpartum-derived cells
US7628977Apr 18, 2003Dec 8, 2009Massachusetts Institute Of TechnologyParticles for inhalation having sustained release properties
US7651853Oct 31, 2007Jan 26, 2010Nsgene A/SCultures of GFAP+ nestin+ cells that differentiate to neurons
US7655463Feb 12, 2008Feb 2, 2010Biogen Idec Ma Inc.Treating neuropathic pain, particularly diabetic peripheral neuropathy, by administering a truncated neublastin polypeptide; activating a RET receptor tyrosine kinase
US7678364Mar 30, 2001Mar 16, 2010Alkermes, Inc.Dry powder; complex
US7727283Mar 4, 2004Jun 1, 2010P Tech, Llc.Tissue stabilizing implant method
US7732129Dec 1, 1998Jun 8, 2010Crucell Holland B.V.use of low-medium perfusion rates in an attached cell culture system to provide for improved yields; improved Ad-p53 production with cells grown in serum-free conditions; offers scalability, validatability and virus purity comparable to that achieved using CsCl gradient ultracentrifugation
US7807150Mar 8, 2004Oct 5, 2010Massachusetts Institute Of TechnologyInjectable composition containing crosslinkable material and cells for forming animal tissue
US7875272Dec 22, 2005Jan 25, 2011Ethicon, IncorporatedTreatment of stroke and other acute neuraldegenerative disorders using postpartum derived cells
US7875273Dec 22, 2005Jan 25, 2011Ethicon, IncorporatedTreatment of Parkinson's disease and related disorders using postpartum derived cells
US7888096Jun 26, 2007Feb 15, 2011Crucell Holland B.V.Liquid adenovirus formulations
US7888097Oct 29, 2007Feb 15, 2011Crucell Holland B.V.Formulation for adenovirus storage
US7892222Jan 12, 2001Feb 22, 2011Beta O 2 Technologies Ltd.Implantable device
US7896880Nov 15, 2001Mar 1, 2011P Tech, LlcApparatus and method for tissue removal
US7897384Sep 8, 2003Mar 1, 2011Ethicon, Inc.Chondrocyte therapeutic delivery system
US7914579Feb 9, 2006Mar 29, 2011Children's Medical Center CorporationTissue engineered tendons and ligaments
US7927599Dec 4, 2008Apr 19, 2011Ethicon, Inc.Chondrocyte therapeutic delivery system
US7951357Jul 13, 2005May 31, 2011Glusense Ltd.Implantable power sources and sensors
US8012500Nov 30, 2004Sep 6, 2011Beta-O2 Technologies Ltd.Implantable device
US8034329Oct 3, 2008Oct 11, 2011Advanced Technologies And Regenerative Medicine, LlcRepair and regeneration of renal tissue using human umbilical cord tissue-derived cells
US8034635Dec 2, 2008Oct 11, 2011Absorber AbMethods of donor specific crossmatching
US8043271Nov 26, 2008Oct 25, 2011Beta 02 Technologies Ltd.Apparatus for transportation of oxygen to implanted cells
US8105793Jul 16, 2008Jan 31, 2012Biomed Solutions, LlcProcess for in vivo treatment of specific biological targets in bodily fluids
US8110213Jul 15, 2008Feb 7, 2012Massachusetts Institute Of TechnologyMethod of forming a tissue structure by introducing cells into an implanted matrix
US8119114Jun 27, 2008Feb 21, 2012Biogen Idec Ma Inc.Polymer conjugates of mutated neublastin
US8153117Aug 10, 2006Apr 10, 2012Depuy Mitek, Inc.Genetically altered chondrocyte expresses a therapeutic agent; implanting a biocompatible substrate into a target region; brain, heart, liver, kidney, intestinal tract, spleen, smooth and skeletal muscles, eye, ganglions, lungs, gonads, pancreas
US8153414Dec 6, 2000Apr 10, 2012Allertein Therapeutics, LlcMicrobial delivery system
US8163714Mar 2, 2005Apr 24, 2012Cellmed AgInjectable crosslinked and uncrosslinked alginates and the use thereof in medicine and in cosmetic surgery
US8163875Apr 16, 2004Apr 24, 2012Biogen Idec Ma Inc.Polymer conjugated glycosylated neublastin
US8173372May 16, 2003May 8, 2012Absorber AbMethods of donor specific crossmatching
US8202701Oct 7, 2005Jun 19, 2012Georgia Tech Research CorporationMicroencapsulation of cells in hydrogels using electrostatic potentials
US8206622 *Feb 22, 2005Jun 26, 2012Eyesense AgProcess for production of ionically crosslinked polysaccharide microspheres
US8217146Dec 7, 2009Jul 10, 2012Biogen Idec Ma Inc.Neurotrophic factors and methods of use thereof
US8236538Dec 17, 2008Aug 7, 2012Advanced Technologies And Regenerative Medicine, LlcMethods for sterilizing materials containing biologically active agents
US8257963May 20, 2008Sep 4, 2012Depuy Mitek, Inc.Chondrocyte container and method of use
US8263553Aug 18, 2005Sep 11, 2012Biogen Idec Ma Inc.Neublastin variants
US8277796Apr 24, 2009Oct 2, 2012Advanced Technologies And Regenerative Medicine, LlcRegeneration and repair of neural tissue using postpartum-derived cells
US8293530Oct 17, 2007Oct 23, 2012Carnegie Mellon UniversityMethod and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom
US8318483Jul 6, 2006Nov 27, 2012Advanced Technologies And Regenerative Medicine, LlcPostpartum cells derived from umbilical cord tissue, and methods of making and using the same
US8329655May 1, 2008Dec 11, 2012Biogen Idec Ma Inc.Methods for increasing vascularization
US8354100Mar 23, 2011Jan 15, 2013Depuy Mitek, Inc.Chondrocyte therapeutic delivery system
US8357666Apr 7, 2009Jan 22, 2013Nupotential, Inc.Reprogramming a cell by inducing a pluripotent gene through RNA interference
US8361459Jan 29, 2010Jan 29, 2013Advanced Technologies And Regenerative Medicine, LlcTreatment of stroke and other acute neural degenerative disorders using postpartum-derived cells
US8367405Apr 12, 2006Feb 5, 2013Mesoblast, Inc.Isolation of adult multipotential cells by tissue non-specific alkaline phosphatase
US8394369Aug 10, 2006Mar 12, 2013Depuy Mitek, Inc.Chondrocyte therapeutic delivery system
US8404264Dec 6, 2011Mar 26, 2013Northwestern UniversityFunctionalizing implantable devices with a poly (diol citrate) polymer
US8431226Mar 29, 2006Apr 30, 2013Biomet Manufacturing Corp.Coated medical device
US8431533 *Sep 22, 2006Apr 30, 2013Biocompatibles Uk Ltd.GLP-1 fusion peptides, their production and use
US8444630Nov 28, 2007May 21, 2013Beta-O2 Technologies Ltd.Oxygen supply for cell transplant and vascularization
US8449919Mar 6, 2006May 28, 2013Bingqian ShenComposition and method for preparing alginate nanocapsules
US8465537Jun 17, 2004Jun 18, 2013Gel-Del Technologies, Inc.Encapsulated or coated stent systems
US8491883Feb 14, 2011Jul 23, 2013Advanced Technologies And Regenerative Medicine, LlcTreatment of amyotrophic lateral sclerosis using umbilical derived cells
US8501467Dec 23, 2009Aug 6, 2013Stemcells California, Inc.Cultures of GFAP+ nestin+ cells that differentiate to neurons
US8507212Jan 10, 2012Aug 13, 2013Biomed Solutions LlcProcess for in vivo treatment of specific biological targets in bodily fluids
US8518390Jul 15, 2011Aug 27, 2013Advanced Technologies And Regenerative Medicine, LlcTreatment of stroke and other acute neural degenerative disorders via intranasal administration of umbilical cord-derived cells
US8529939Dec 8, 2004Sep 10, 2013Gel-Del Technologies, Inc.Purified protein(s) combined with drug(s) and biocompatible solvent(s) to form a coatable mixture; reduction to form a cohesive body or solidified cohesive mass that is formed into a mucoadhesive device havinghomogenous distribution; ovalbumin combined with glycerol; bonding strength
US8529956Apr 17, 2008Sep 10, 2013Carnell Therapeutics CorporationBlood-derived plastic bone tissue articles; Young's Modulus of 0.03 GPa to 50 GPa; article; biological response modifiers hormones, growth factors, cytokines, extracellular matrix molecules; crosslinking agents iridoid derivatives, diimidates, diones; plasticizers phthalate, adipate, plant oils, glycols
US8529958Jul 6, 2011Sep 10, 2013Carmell Therapeutics CorporationMethods and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom
US8529959Jul 6, 2011Sep 10, 2013Carmell Therapeutics CorporationMethods and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom
US8529960Jul 6, 2011Sep 10, 2013Carnell Therapeutics CorporationMethods and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom
US8529961Jul 6, 2011Sep 10, 2013Carmell Therapeutics CorporationMethods and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom
US8541232Mar 8, 2007Sep 24, 2013Kwalata Trading LimitedComposition comprising a progenitor/precursor cell population
US8551775Nov 11, 2010Oct 8, 2013Vbi Technologies, L.L.C.Subpopulations of spore-like cells and uses thereof
US8574897Jun 8, 2012Nov 5, 2013DePuy Synthes Products, LLCMethods for sterilizing materials containing biologically active agents
US8592201Aug 6, 2012Nov 26, 2013Depuy Mitek, LlcChondrocyte container and method of use
US8597906Apr 26, 2011Dec 3, 2013Oxyrane Uk LimitedGlycosylation of molecules
US8623393Apr 29, 2003Jan 7, 2014Gel-Del Technologies, Inc.Biomatrix structural containment and fixation systems and methods of use thereof
US8642732Mar 21, 2012Feb 4, 2014Biogen Idec Ma Inc.Polymer-conjugated glycosylated neublastin
US8658152Sep 6, 2012Feb 25, 2014DePuy Synthes Products, LLCRegeneration and repair of neural tissue using postpartum-derived cells
US8685724Jun 1, 2005Apr 1, 2014Kwalata Trading LimitedIn vitro techniques for use with stem cells
US8686154Jun 10, 2009Apr 1, 2014Emisphere Technologies, Inc.Compounds and compositions for delivering active agents
US8703121Jun 25, 2004Apr 22, 2014DePuy Synthes Products, LLCPostpartum-derived cells for use in treatment of disease of the heart and circulatory system
US8722034Mar 26, 2010May 13, 2014Depuy Synthes Products LlchUTC as therapy for Alzheimer's disease
US8722862Aug 18, 2005May 13, 2014Biogen Idec Ma Inc.Refolding transforming growth factor beta family proteins
US8741638Dec 19, 2006Jun 3, 2014DePuy Synthes Products, LLCIn vitro expansion of postpartum-derived cells in roller bottles
US8758796Mar 21, 2013Jun 24, 2014Northwestern UniversityFunctionalizing implantable devices with a poly (diol citrate) polymer
US8790637Mar 25, 2008Jul 29, 2014DePuy Synthes Products, LLCRepair and regeneration of ocular tissue using postpartum-derived cells
US8790705 *Apr 27, 2007Jul 29, 2014Biocompatibles Uk Ltd.Spherical microcapsules comprising GLP-1 peptides, their production and use
US8815585Jun 30, 2008Aug 26, 2014Cellular Dynamics International, Inc.Automated method and apparatus for embryonic stem cell culture
US8815587Nov 15, 2010Aug 26, 2014DePuy Synthes Products, LLCPostpartum cells derived from umbilical tissue and methods of making and using the same
US8821431Sep 7, 2008Sep 2, 2014Beta O2 Technologies Ltd.Air gap for supporting cells
US20110130329 *Sep 22, 2006Jun 2, 2011Peter GeigleGlp-1 Fusion Peptides, Their Production and Use
US20120238497 *May 29, 2012Sep 20, 2012Peter GeigleGlp-1 fusion peptides, their production and use
USRE34326 *Nov 14, 1990Jul 27, 1993British Technology Group, USA, Inc.Polyurethanes
USRE35653 *Jun 30, 1993Nov 4, 1997Brown University Research FoundationIn vivo delivery of neurotransmitters by implanted, encapsulated cells
USRE35862 *Aug 14, 1987Jul 28, 1998Emisphere Technologies, Inc.Delivery systems for pharmacological agents encapsulated with proteinoids
USRE38027 *Jun 30, 1999Mar 11, 2003The Rogosin InstitutePreparation of agarose coated, solid agarose-collagen beads containing secretory cells
USRE39542 *Jan 2, 2003Apr 3, 2007The Rogosin InstitutePreparation of agarose coated, solid agarose-collagen beads containing secretory cells
USRE40555 *Nov 1, 2004Oct 28, 2008The Rogosin InstitutePreparation of agarose coated, solid agarose beads containing secretory cells
USRE42479Feb 19, 2004Jun 21, 2011Children's Medical Center CorporationEngineering of strong, pliable tissues
USRE42575Sep 28, 2006Jul 26, 2011Children's Medical Center CorporationEngineering of strong, pliable tissues
DE3432143A1 *Aug 31, 1984Mar 21, 1985Damon Biotech IncVerfahren zur einkapselung eines einzuhuellenden materials
DE3504715A1 *Feb 12, 1985Sep 5, 1985Damon Biotech IncVerfahren und medium zur foerderung der proteinproduktion von saeugerzellen
DE3504724A1 *Feb 12, 1985Sep 5, 1985Damon Biotech IncVerfahren zur einkapselung eines einzuhuellenden materials
DE3504748A1 *Feb 12, 1985Sep 5, 1985Damon Biotech IncVerfahren zur kultivierung von zellen in hoher dichte
DE3509210A1 *Mar 14, 1985Nov 28, 1985Damon Biotech IncVerfahren zum screening von zellkulturen zur selektion von bestimmte substanzen sezernierenden zellen
DE102004019241A1 *Apr 16, 2004Nov 3, 2005Cellmed AgInjizierbare vernetzte und unvernetzte Alginate und ihre Verwendung in der Medizin und in der ästhetischen Chirurgie
EP0126537A2 *Apr 6, 1984Nov 28, 1984Damon Biotech, Inc.Sustained release capsule and process of making it
EP0127713A2 *Jun 9, 1983Dec 12, 1984Connaught Laboratories LimitedMicroencapsulation of living tissue and cells
EP0127989A2 *May 25, 1984Dec 12, 1984Connaught Laboratories LimitedMicroencapsulation of living tissue and cells
EP0167690A2 *Aug 8, 1984Jan 15, 1986Connaught Laboratories LimitedDroplet generation
EP0199362A2 *Apr 25, 1986Oct 29, 1986Massachusetts Institute Of TechnologySystem and apparatus for delayed and pulsed release of biologically active substances
EP0301777A1 *Jul 22, 1988Feb 1, 1989Queen's University At KingstonMultiple membrane microencapsulation
EP0529659A2 *Aug 28, 1992Mar 3, 1993Seikagaku Kogyo Kabushiki Kaisha (Seikagaku Corporation)Agent for forming spheroids of hepatocytes and process for culturing hepatocytes for formation of spheroids
EP0553195A1 *Sep 25, 1991Aug 4, 1993Univ TexasBiocompatible microcapsules.
EP0754462A2 *Jul 2, 1996Jan 22, 1997TTI Co., Ltd.Auxiliary liver with long term storability and production thereof
EP0762874A1 *Dec 30, 1992Mar 19, 1997Clover Consolidated LtdCytoprotective, biocompatible, retrievable macrocapsule containment systems for biologically active materials
EP1503198A1 *Jun 22, 2004Feb 2, 2005Robert Bosch GmbhAcitve sensor channel
EP1972324A1 *Mar 21, 2007Sep 24, 2008Cognis IP Management GmbHEncapsulated liposomes
EP1992336A2 *Aug 6, 2003Nov 19, 2008DA VolterraDosage form for the administration of active agents in the colon
EP2025353A2Apr 29, 1994Feb 18, 2009Massachusetts Institute of TechnologyInjectable polysaccharide-cell compositions
EP2075254A1Mar 30, 2005Jul 1, 2009NsGene A/STherapeutic use of a growth factor, NsG33
EP2093256A2Jul 28, 2006Aug 26, 2009Carnegie Mellon UniversityBiocompatible polymers and methods of use
EP2289911A2Mar 30, 2005Mar 2, 2011NsGene A/STherapeutic use of a growth factor, NsG33
EP2290079A2Jul 5, 1999Mar 2, 2011NsGene A/SNeurotrophic factors
EP2322599A2Jun 25, 2004May 18, 2011Ethicon, IncorporatedPostpartum cells derived from umbilical cord tissue and methods of making and using the same for repair and regeneration of soft tissue
EP2336298A2Jun 25, 2004Jun 22, 2011Ethicon, IncorporatedPostpartum cells derived from placental tissue and methods of making and using the same
EP2341131A2Jun 25, 2004Jul 6, 2011Ethicon, IncorporatedRepair and regeneration of cartilage and bone using postpartum-derived cells
EP2348105A1Sep 26, 2005Jul 27, 2011Angioblast Systems IncorporatedMultipotential expanded mesenchymal precursor cell progeny (MEMP) and uses thereof
EP2360242A1Jun 29, 2005Aug 24, 2011Angioblast Systems, Inc.Method of enhancing proliferation and/or survival of mesenchymal procursor cells (MPC)
EP2361970A1Jun 29, 2005Aug 31, 2011Angioblast Systems IncorporatedMethod of enhancing proliferation and/or survival of mesenchymal precursor cells (MPC)
EP2399991A1Apr 12, 2006Dec 28, 2011Angioblast Systems IncorporatedIsolation of adult multipotential cells by tissue non-specific alkaline phosphatase
EP2508612A2Apr 3, 2008Oct 10, 2012Oxyrane UK LimitedGlycosylation of molecules
EP2508614A2Apr 3, 2008Oct 10, 2012Oxyrane UK LimitedGlycosylation of molecules
EP2532356A1Jul 13, 2005Dec 12, 2012Glusense Ltd.Implantable power sources and sensors
EP2609930A2Feb 27, 2007Jul 3, 2013Biogen Idec MA Inc.Treatments for neurological disorders
WO1985005630A1 *May 8, 1985Dec 19, 1985Karyon Technology IncTissue culture and production in permeable gels
WO1986002093A1 *Oct 2, 1985Apr 10, 1986Leonard B TorobinHollow porous microsphere bioreactors and biochemical processes using same
WO1987000197A1 *Jun 5, 1986Jan 15, 1987Karyon Technology IncEntrapment of anchorage-dependent cells
WO1989004657A1 *Nov 3, 1988Jun 1, 1989Damon Biotech IncSustained release of encapsulated molecules
WO1990007468A1 *Dec 22, 1989Jul 12, 1990Bio Recovery Systems IncRecovery of heavy and precious metals from aqueous solutions
WO1990010063A1 *Feb 15, 1990Aug 22, 1990BiosysMethod and medium for packaging entomogenous nematodes
WO1991001680A1 *Aug 13, 1990Feb 12, 1991Palti Yoram ProfSystem for monitoring and controlling blood glucose
WO1991005859A1 *Oct 18, 1990Apr 19, 1991Us CommercePolymer bead containing immobilized metal extractant
WO1991007951A1 *Dec 4, 1990Jun 13, 1991Trancel CorpHomologous guluronic acid alginate coating composition for in-vivo application and implantation and method of using same
WO1991009119A1 *Dec 10, 1990Jun 27, 1991Trancel CorpImproved alginate microcapsules, methods of making and using same
WO1992006678A1Sep 25, 1991Apr 30, 1992Univ TexasBiocompatible microcapsules
WO1992012234A1 *Mar 29, 1991Jul 1, 1992Pioneer Hi Bred IntDried, rotary disc fatty acid microencapsulated bacteria
WO1993017094A1 *Feb 2, 1993Sep 2, 1993Pioneer Hi Bred IntDried, rotary disc microspheres of microorganisms
WO1993019700A1 *Mar 25, 1993Oct 14, 1993Baxter IntSystems and methods for cell implants
WO1993019701A1 *Mar 25, 1993Oct 14, 1994Baxter IntAngiogenic tissue implant systems and methods
WO1993021266A1 *Apr 1, 1993Oct 28, 1993Clover Cons LtdCrosslinked biocompatible encapsulation compositions and methods
WO1994023832A1 *Apr 13, 1994Oct 27, 1994ColeticaUse of a transacylation reaction between an esterified polysaccharide and a polyamine to form a membrane at least on the surface of gelled particles in an aqueous medium, resulting particles, preparation methods therefor and compositions containing same
WO1995019840A1 *Jan 13, 1995Jul 27, 1995Univ CaliforniaMicrocapsule generating system and method of using same
WO1995024168A1 *Feb 23, 1995Sep 14, 1995Univ CaliforniaIn situ dissolution of alginate coatings of biological tissue transplants
WO1995028227A1 *Apr 17, 1995Oct 26, 1995Fred H ClarkAqueous solvent encapsulation method, apparatus and microcapsules
WO1995028480A1 *Apr 12, 1995Oct 26, 1995Biohybrid Tech IncMethods of use of uncoated gel particles
WO1995029667A1 *Mar 30, 1995Nov 9, 1995Univ CaliforniaSpin encapsulation apparatus and method of use
WO1996031223A1 *Apr 5, 1996Oct 10, 1996Univ EmoryMethod of pretreating viable tissue or cells to be contained within a semipermeable vessel
WO1998010061A2 *Sep 5, 1997Mar 12, 1998Bay Zoltan Alkalmazott KutatasMethod and immobilized biocatalyst for the production of l(-) malic acid
WO1998025653A2Dec 10, 1997Jun 18, 1998Anthony AtalaImproved hydrogel for tissue engineering
WO1999048480A2 *Mar 12, 1999Sep 30, 1999Aventis Res & Tech Gmbh & CoMethod for the production of micro capsules
WO1999055252A1Apr 22, 1999Nov 4, 1999Univ MassachusettsGuided development and support of hydrogel-cell compositions
WO2000027207A1Nov 9, 1999May 18, 2000Rogosin InstCompositions of restricted cells capable of rapid growth which produce proliferation suppressive materials, and uses thereof
WO2000054786A1 *Mar 15, 2000Sep 21, 2000Modex Therapeutiques S AMethods and compositions for tolerizing hosts for long term survival of tissue transplants
WO2001050983A1Jan 12, 2001Jul 19, 2001Beta O 2 Technologies LtdImplantable device
WO2004047977A1 *Nov 18, 2003Jun 10, 2004Capsulution Nanoscience AgMethod for modifying microparticles and device for modifying microparticles
WO2005026320A2Aug 9, 2004Mar 24, 2005Rogosin InstEntrapped stem cells and uses thereof
WO2008127423A2 *Nov 14, 2007Oct 23, 2008Cornell Res Foundation IncMicroencapsulated catalyst systems
WO2009126251A2Apr 7, 2009Oct 15, 2009Nupotential, Inc.Reprogramming a cell by inducing a pluripotent gene through use of an hdac modulator
WO2010075500A1Dec 23, 2009Jul 1, 2010Stemcells California, IncTarget populations of oligodendrocyte precursor cells and methods of making and using same
WO2010142007A1Nov 11, 2009Dec 16, 2010Universidade Bandeirante De São Paulo - Academia Paulista Anchieta S/C LtdaPharmaceutical composition and use of the pharmaceutical composition for the treatment, prophylaxis or prevention of neoplastic diseases in humans and animals
WO2011039634A2Sep 29, 2010Apr 7, 2011Universiteit GentHydrolysis of mannose-1-phospho-6-mannose linkage to phospho-6-mannose
WO2011060135A1Nov 11, 2010May 19, 2011Vbi Technologies, LlcSubpopulations of spore-like cells and uses thereof
WO2011061629A2Nov 19, 2010May 26, 2011Oxyrane Uk LimitedYeast strains producing mammalian-like complex n-glycans
WO2012027494A1Aug 24, 2011Mar 1, 2012Regents Of The University Of MinnesotaBispecific targeting reagents
WO2012041328A1Sep 30, 2011Apr 5, 2012Nsgene A/SUse of meteorin for the treatment of allodynia, hyperalgesia, spontaneous pain and phantom pain
WO2012042386A2Sep 29, 2011Apr 5, 2012Oxyrane Uk LimitedMannosidases capable of uncapping mannose-1-phospho-6-mannose linkages and demannosylating phosphorylated n-glycans and methods of facilitating mammalian cellular uptake of glycoproteins
WO2012042387A2Sep 29, 2011Apr 5, 2012Oxyrane Uk LimitedDe-mannosylation of phosphorylated n-glycans
WO2012112982A2Feb 20, 2012Aug 23, 2012Massachusetts Institute Of TechnologyHydrogel encapsulated cells and anti-inflammatory drugs
WO2012167223A1Jun 4, 2012Dec 6, 2012Massachusetts Institute Of TechnologyModified alginates for cell encapsulation and cell therapy
WO2013023013A1 *Aug 9, 2012Feb 14, 2013Wake Forest University Health SciencesCo-encapsulation of live cells with oxygen-generating particles
WO2013136189A2Mar 14, 2013Sep 19, 2013Oxyrane Uk LimitedMethods and materials for treatment of pompe's disease
WO2013151725A1Mar 14, 2013Oct 10, 2013The Regents Of The University Of CaliforniaRegenerative sera cells and mesenchymal stem cells
WO2013171736A1Apr 29, 2013Nov 21, 2013Cartiheal(2009) LtdBiomatrix hydrogels and methods of use thereof
WO2014136065A2Mar 5, 2014Sep 12, 2014Oxyrane Uk LimitedProduction of catalytically active type i sulfatase
Classifications
U.S. Classification435/178, 424/496, 424/424, 435/175, 424/94.3, 424/497, 435/182, 264/4, 435/382
International ClassificationA61K35/50, B01J13/14, A61J3/07, A61K38/00, C12P21/04, C12N11/04, B01J13/04, A61L27/36, A01N1/02, A61L27/20, A61K35/407, C12N1/00, B01J20/32, A61K31/44, A61K9/62, C12N5/02, A61K39/44, A61K38/43, A61K9/16, A01N1/00, A61F2/02, A61K35/12, A61K33/44, A61L27/00, A61K38/28, B01J13/16, C12N5/00, B01J13/08, A61K35/39, A61K9/50, C12N11/02, C12N5/071
Cooperative ClassificationB01J13/08, A01N1/0231, B01J13/16, A61K2035/128, A61K9/5031, A61K9/5073, C12N2533/74, A61K39/44, C12N11/04, A61F2/022, C12N5/0677, A61K9/1652, A61L27/20, A61K38/00, B01J13/14, B01J13/04, C12N2533/30, A61K35/39, C12N2533/32, C12N5/0671, A01N1/02, A61L27/36, C12N5/0012, A61K9/5036
European ClassificationC12N5/06B14A, A61K35/12, A61L27/20, B01J13/16, A61L27/36, A01N1/02, A61K9/50H6D, A61K9/16H6F, A61F2/02B, C12N5/00C, C12N5/06B22A, A61K9/50H6F, B01J13/08, A61K39/44, B01J13/04, C12N11/04, B01J13/14, A61K9/50K, A01N1/02C4
Legal Events
DateCodeEventDescription
Jun 17, 1992ASAssignment
Owner name: REPLIGEN CORPORATION A CORP. OF DELAWARE, MASSA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:ABBOTT BIOTECH, INC. A CORP. OF DELAWARE;REEL/FRAME:006144/0978
Effective date: 19920514
Oct 4, 1983ASAssignment
Owner name: DAMON BIOTECH, INC., 119 FOURTH AVENUE, NEEDHAM HE
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:DAMON CORPORATION;REEL/FRAME:004188/0916
Effective date: 19830926